Garcinia complex adams
Just preventing further weight gain is an accomplishment for some people.” The biggest problem with garcinia cambogia, Heymsfield says, besides being a waste of money, is that it distracts people from concentrating on the important things when it comes to weight loss: increasing your activity level and eating a healthier diet.
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The Easiest Way To Lose 17 Pounds In 7 Days
ok – so you want to lose weight , and no bones about it – you want to do it fast.
What’s not possible is losing like 50 pounds in the matter of a few hours… unless you do some serious liposuction surgery.
But if you’re looking for a powerful plan to lose weight, get rid of belly fat, and fit into your skinny jeans in the nick of time – you’ve come to the right place.
Because I’m going to be honest up front – if you really want to lose weight fast, you’re going to have to do some work, and you’re going to have to follow this plan.
So what is the plan? Good question.
What Is The Plan?
What I’m talking about here is combining a strict diet plan with proper exercise. That’s the absolute best way to lose weight – and to lose weight naturally.
There are a few huge rules. First and foremost – never skip meals or eat at irregular times. You want to hit every meal and eat it at the right time – consistency is key (1).
Second, make sure that your weight loss goal is realistic. If you weigh 300 pounds and want to lose 20 pounds in a narrow timeframe – that’s way more realistic than weighing 120 pounds and wanting to lose 20 pounds in a narrow timeframe (2).
It’s all about what your body can do and what your limits are. The most important thing with diet and exercise is that it’s safe diet and exercise.
Of course, you still have to pick the right diet plan. That’s why I want to talk about one of my favorites.
The Right Diet Plan To Lose 17 Pounds In 7 Days
One of my favorite diet plans (and one of the most popular) is the gm diet plan – or the General Motors diet plan (3). Yes – the same general motors as the car manufacturer. I know, it’s weird, lets’ move on. This gm diet plan works for all age groups, and people have lost up to 17 pounds in a single week by following it. If you want to follow it, you have to be prepared. This is a strict diet plan – and it requires a lot of discipline on your part. If you want it to work, and you want to lose up to 17 pounds in a week, you’re going to have to have your mind right before you start.
How do you get your mind right? Well, first, you have to accept one very important point – the fastest way to lose weight is by not being hungry.
If you’re hungry, your craving for junk food will go through the roof. That’s going to undermine any diet or weight loss plan.
Therefore, you have to make sure to pick a plan that doesn’t require that you go hungry – and the gm plan is it.
It’s a 7 day plan that will require discipline – but also help you hit your weight loss goals. Let’s start:
GM Diet Day 1
ok – this is the gateway to your diet, the door you step through – and therefore it’s the most important day. Treat it accordingly.
The first day of the gm diet is an all fruit day. That’s right, you heard me correctly – all fruit all the time.
You can eat all the fruit that you want and eat it whenever you want. Fill up on fruit, and then some.
There are literally no restrictions – except one. Do not eat bananas on the first day of the gm diet. Stick to fruits like watermelon and cantaloupe.
At the same time, you want to drink at least 8 glasses of water. Try to go for 12 to get the full effect.
Remember, on day one, you’re eating nothing but fruit. That means no grains, no meat, no dairy, and no vegetables. If you get hungry, eat more fruit and drink more water.
GM Diet Day 2
Day one was all about fruits. Day 2 is all about vegetables.
You’re going to want to eat vegetables and only vegetables on day two. It doesn’t matter whether they’re raw or cooked – it only matters that you’re only eating vegetables.
However, one very important thing to remember is that these vegetables can not be cooked in oil. If you’re going to cook them, you should boil or steam them instead.
Also remember to keep up your water consumption. You’re looking for at least 8-12 glasses on day 2.
GM Diet Day 3
On day 3, you’re going to be combining the rules of day 1 and day 2 – and eating only fruits and vegetables for the entire day. No potatoes and no bananas – strictly the fruits and veggies you had access to on day 1 and day 2.
Either eat all fruit in the morning, veggies in the afternoon, and fruit in the evening – or go veggies in the morning, fruit in the afternoon, and veggies in the evening – whatever you prefer.
Keep up drinking water! 8-12 glasses, minimum.
GM Diet Day 4
This is the first day that you’re going to switch things up.
On day 4, all you should eat is bananas. That’s it – just bananas. Eat a minimum of 8-10 bananas over the course of the day.
Also extremely important on day 4 is to drink 3 glasses of milk, and water whenever you’re thirsty. Space out the milk over the course of the day.
Whenever you’re hungry – eat a banana. If you eat all 8 to 10 bananas over the course of the day, you won’t feel hungry – just space them out.
GM Diet Day 5
Switching things up again, day 5 is all about tomatoes and rice. Eat a cup of rice for lunch, and eat at least 6 to 7 tomatoes over the course of the day.
Remember – this will produce a lot of uric acid in your body. Therefore, you should up your water consumption.
Aim for at least 12 to 15 glasses of water on day 5 and you’ll be golden.
GM Diet Day 6
On day 6, you’ll be eating a cup of rice for lunch again – and combining that with vegetables all day. Stick to an all vegetable diet on day 6.
This is actually the most crucial day of the entire diet for water, so you absolutely must make sure to drink at least 8-12 glasses of water on day 6. If you can do that, you’re almost done!
GM Diet Day 7
This is it, the last day! You made it!
On the last day of the gm diet, you can eat a cup of rice for lunch. Other than that, you want to stick with an all vegetable diet for the rest of the day.
To drink, you can drink all the fruit juice that you want. This will flush your digestive system fully and leave your body in the optimum state.
If you can follow this diet to the letter – you will see a considerable amount of weight loss in just a week. People have reported up to 17 pounds of weight loss – how much did you lose?
First of all, before any of you even think of trying this, be forewarned about ANY diet that focused mainly on one food group with the exclusion of another.
The MAJOR flaw I see in this is there is absolutely NO PROTEIN in this program, very minimal to no fats, and very VERY low carbs. There is no balance to the meals or portions. I would like to know exactly what science this diet has been based upon?
With my degree in Health and Wellness and Personal Training certifications, one specifically for weight management, there is nothing here that is scientifically supported.
This is a FAD diet. Fad diets only set you up to gain all the weight you lost PLUS some! The weight you are losing on these kinds of diets is water weight PLUS lean muscle mass. You don’t want to lose water or muscle because those are the very things you need to INCREASE your metabolism. Please research diets carefully to be sure they adhere to sound basic food science and daily recommended dietary intake protocols.
In order to lose weight you must have a balance of proteins, carbs, and fats and exercise 3 or more times per week. In order to track your dietary intake I highly recommend using websites and apps such as MyFitnessPal. These websites provide sound dietary information, awesome health tracking tools, and a great support system to help you achieve your goals.
Can I add salt to the vegetable and rice not a lot but just so it not to bland
10 day diet for me
Very informative article, If someone needs more info about weight loss in 7 days.,
you can find here
I’m sooo grateful for this diet. I’m on my fifth day and I’ve lost 5lbs already.. I cheated a little here and there, and still lost a pound a day. I will be starting over when i finish, only this time i will stick to the plan without cheating. Thank you soo much for posting this diet plan.
I am sooo greatful for this diet. I’m on my fifth day andlost 5lbs already. I cheated a little each day and still saw results and i felt great. When I’m finished i will be starting over with this diet again this time i will stick to the plan without cheating. Thank you soo much for posting this diet plan.
Is there any one who have achieved the desired results.
So I’m on the last day of this plan and I lost 6.5lbs. Not as much as I’d hoped but still happy with the loss. What do I do now? I want to lose another 15 pounds and I have about a month to do it.
Started this diet today. I didn’t do really well on day one but I’m still continue doing it and will tell you guys my results. I’m 143 pounds and I want to be around 136
The Bananas made me not feel good all day yuck. I wish I had something else to eat instead. Hopefully it’s all worth it in the end. I guess I’ll drink more water in the meantime
Can you still achieve the results across 6 days as holiday starts day 7 wondering whether it’s worth doing if can’t commit to the full 7 days ?
I can not drink milk. Is there anything that I could drink or eat to replace that. Thank you in advance.
Is this a blogger page interested in more tip and to do’s ;)?
Is there a substitution for tomatoes?what type of rice is better ?
Okay I am starting this diet today and I want to know is does it really work? And what was the highest amount of weight did someone lose?
I just started day 4 and it’s working so far. Im down 10lbs already. I do go to the gym and do some light cardio.
End Results: I completed this diet. The only thing that I could not do was drink 12-15 glasses of water on tomato day; I drank 9. I am 200 pounds, 5’8″ and would like to weigh 170. I lost only 6 pounds; the first 5 of course being water.
What is missing from this diet is the activity portion while dieting and how to re-introduce foods to your body after Day 7.
If you add 20-25 mins of cardio twice a day, you will see great result. Your time starts once your heart rate reaches 140. So for example, if your choice of cardio is the treadmill, then you find a speed that gets your your heart rate up to 140, not exceeding 150. This should take no more than 2 mins max to achieve. Once you have reached your desired heart rate and speed, that is when your 20-25 min. cardio timer should begin.
Re-Intro on Day 8 and everyday after can can be tricky if planned correctly. As with any desire, it is always best to in vision the goal but its after life. If it is your goal to 30 lbs., what happens once you get there? Do you want to maintain that weight? And if so, what does that lifestyle look like? Its important that you give that same energy to the after life and plan accordingly….work it backwards. Know if you want to do a complete revamp of your lifestyle. You have to decide if you are going to continue to eat clean. Whether you are going to be a vegan, eat or cut out red meat, beef or pork! It has to be decided prior to participating in ANY diet. Doing this will not only help you in your choosing of the right diet, it will be a welcomed introduction to your new lifestyle.
Best of Luck to you! And remember that the best commitment one can ever make is the one we make to ourselves.
End Results: I completed this diet. The only thing that I could not do was drink 12-15 glasses of water on tomato day; I drank 9. I am 200 pounds, 5’8″ and would like to weigh 170. I lost 6 pounds; the first 5 of course being water.
Okay so I’m about to start this diet today. If you want to know my results add my Snapchat @airy_kid I weigh 130 and I’m 5’5 so let’s see what we get to next Thursday.
I have now lost 17 pounds with garcinia cambogia (I hope to lose another 15 pounds or so.) I have not followed any diet plan and have been pretty much eating what I want. I have cut out soda and have been drinking only water. I do not buy potato chips because I am not good at portion control with them. I did splurge a little during the holidays but did not put on any weight. I have not done any aerobic exercise. Hope to add indoor biking soon. This product works for me and it can work for you too. I followed advice from here:
Garcinia cambogia is an aid and you will not loss weight by simply taking it while you continue to eat whatever you want. That is completely false.
Garcinia complex adams
Human Pathology Digital Image Gallery
CONJUGATED BILIRUBIN: Bilirubin that has been conjugated to glucuronic acid, making it water-soluble
CONFLUENT-LYTIC NECROSIS: Death of clusters of hepatocytes (* attributed in the current literature to humoral immunity)
COUNCILMAN (ACIDOPHIL) BODY: Single-cell necrosis (apoptosis) of a hepatocyte, typically in hepatitis as a result of attack by a T-killer cell.
* CYTOPLASMIC DISSOCIATION means edema at the edges of a hepatocyte, granular cytoplasm around its nucleus. The cell is injured.
FOCAL NECROSIS: Death of individual cells, evidenced either by Councilman bodies or lytic necrosis (i.e., collapse seen on reticulin stain). Inside the lobule, it's "focal lobular necrosis", as in smoldering hepatitis from any cause.
* FEATHERY DEGENERATION: A pattern seen when a liver cell retains both bile salts and water. Ask a physical chemist how the detergent effect of bile salts causes it. When the bile actually digests a group of liver cells, it's called a BILE INFARCT (misnomer, of course). Leave recognizing these to us.
GIANT MITOCHONDRIA (megamitochondria): Monsters seen in hepatocytes in alcoholism (sometimes NASH). They are d-PAS negative (lets you distinguish them from alpha-1 antitrypsin). See J. Clin. Path. 45: 412, 1992.
* "Yokoo bodies." These mitochondria may have suffered a characteristic loss of DNA due to alcohol-induced free-oxygen-radical damage or something; the deletion makes it harder for the liver cell to burn fat, and so forth (Gastroent. 108: 193, 1995.)
GROUND GLASS HEPATOCYTES: Distinctive hepatocytes seen in chronic (not acute) hepatitis B infection. The "ground glass" cytoplasm is an unusual accumulation of a cytokeratin (Hepatology 28: 347, 1998).
HEPATOCELLULAR JAUNDICE: Jaundice due primarily to failure of hepatocytes to properly take up / conjugate bilirubin.
HEMOLYTIC JAUNDICE: Jaundice due to excessive destruction of red cells or their precursors at any site
* HELLP SYNDROME: Hemolysis, elevated liver enzymes, low platelets. A poorly-understood and very serious complication of pregnancy. Seizure and hypertension management, glucocorticoids, and/or exchange transfusions may be required. More about this later.
INTERFACE HEPATITIS: Necrosis of groups of hepatocytes within the limiting plate. The term has replaced "piecemeal necrosis", to prevent confusion with focal necrosis deeper within the lobule. Often the only evidence of "necrosis" that you see is a little area with collapsed architecture (reticulin stain shows the collapse); if you're lucky, you may spot a Councilman body.
INTERLOBULAR BILE DUCT: The big bile duct in the portal tract. It runs with the branch of the hepatic artery.
JAUNDICE: Too much bilirubin (conjugated or not) in the bloodstream, for any reason
LIMITING PLATE: The row of hepatocytes immediately adjacent to the portal tract. It should be smooth and uniform.
* NONSPECIFIC REACTIVE HEPATITIS ("liver cell unrest"): Increased prominence of Kupffer cells and increased ploidy of many hepatocytes. This is a non-specific finding, common to many (if not most) serious illnesses affecting the entire body.
LOBULAR DISARRAY: Loss of the normal radial arrangement of liver plates within the lobule, typically with severe distortion of the sinusoids. The hallmark of acute hepatitis.
LUPOID HEPATITIS: An unfortunate term for the several kinds of non-viral (?), autoimmune hepatitis in which the histology is that of chronic hepatitis, usually with a lot more plasma cells than in the viral forms (worth remembering).
LYTIC NECROSIS: The hepatocytes in a region (large or small) are gone, leaving behind collapsed stroma. Older references call this "dropout necrosis".
MALLORY'S HYALINE: Masses ("rope-like", "cottage cheese", "Mallory-Denk bodies") of altered cytokeratin and cell stress proteins (ubiquitin, others: Arch. Path. Lab. Med. 114: 589, 1990). Usually (but not always) a marker for alcoholic hepatitis / severe NASH.
MASSIVE NECROSIS: Most of the hepatocytes on the slide are dead. Due to poisoning, viruses, medication reactions, or ischemia. SUBMASSIVE NECROSIS means that at least some entire lobules are destroyed, but in other lobules, enough cells are alive.
MACROVESICULAR FAT: One large lipid drop in a hepatocyte, pushing the nucleus to one side
MICROVESICULAR FAT: Several lipid drops in a hepatocyte; the nucleus stays in the center
OBSTRUCTIVE JAUNDICE: Cholestatic jaundice caused by mechanical obstruction of the common bile duct or hepatic ducts. Also called SURGICAL / SURGEON'S JAUNDICE; all other forms of jaundice are MEDICAL / INTERNIST'S JAUNDICE.
* ONCOCYTIC HEPATOCYTES (oxyphilic hepatocytes, i.e., mitochondrion-packed) are common in many livers, especially where there's been a lot of regeneration, i.e., cirrhosis, which has let mutant mitochondria overgrow (Virch. Arch. 432: 349, 1998). Fibrolamellar hepatocellular carcinomas are also mitochondrion-packed.
Is life worth living? It depends on the liver!
The liver is usually our heaviest internal organ, and the most durable. Unlike lungs, kidneys, heart, and brain, the livers of most 100-year-olds are morphologically and functionally normal.
Liver pathology includes only a few common diseases. The terminology and morphology of these lesions are notoriously confusing for beginners. Further, you'll have to know them, because liver biopsy is fairly common, especially in this era of managing chronic hepatitis by biopsy results.
It would be best for you to start by learning the definitions in the "Glossary", and making note of the material under "For Future Liver Pathologists".
You already know that the liver is the great chemical plant of the body. You remember its location, its anatomic relationships, its blood supply, and its essential architecture.
Worth mentioning: The STELLATE CELLS ("Ito cells", "perisinusoidal cells") sit in the space of Disse, store vitamin A, and turn on to carry out fibrosis of the hepatic lobule in developing cirrhosis.
* Future pathologists: See them with CRBP-1 or alpha-SMA.
* Possbly the most interesting recent work on liver pathology is the finding that signals from hepatocytes in their death-throes stimulate both hepatocyte progenitors and myofibroblsts / stellate cells / laminin producers to handle the re-growth (Gut 59: 645 & 655, 2010) The new hope is that natural killer cells can be activated by biotech products to destroy the proliferating stellate cells (Gut 60: 90, 2011) or at least suppress them (Dig. Dis. Sci. 55: 261, 2010; Gastroenterology 138: 347, 2010).
Normal adult livers weigh 1400-1600 gm. Liver weight is widely variable at autopsy. I've autopsied an end-stage cirrhotic with a 700 gm liver, and an alcoholic with a 7000 gm liver. The liver HURTS when, and only when, its capsule is stretched.
Despite the discussion in "Big Robbins", the normal liver may or may not be palpable, depending on its shape. Maybe 1% of livers have a "Riedel's lobe" easily felt on the right side; this is simply an anatomic variant of no importance to one's health. Others have a small right lobe and a large left lobe, while still others have random grooves across the organ ("hepar lobatum", or one variant). The hyperinflated lungs of the emphysema patient usually push the liver downward and make the edge palpable, but again, this is not reliable; "rib marks" (really from muscle pressure) in emphysema produce the familiar LEIBERMEISTER GROOVES. Remember that a newborn's liver edge is usually easily palpable 1-2 cm below the costal arch.
The histology of the liver is worth reviewing. Remember that the METABOLIC LOBULE ("ACINUS") is centered on the portal areas, and the CLASSICAL LOBULE is centered on the central vein. Whichever system you use, ZONE 1 is the hepatocytes near the portal areas, ZONE 2 is the hepatocytes midway between the portal areas and central veins, and ZONE 3 is the hepatocytes around the central veins.
The familiar polyhedral, pink-staining hepatocytes are often (maybe 10%) binucleate or tetraploid / octoploid. This is normal. You remember the architecture of the liver plates and sinusoids, the passage of bile from canaliculi to canals of Hering to bile ducts, and the appearance and function of the hepatic endothelium and Kupffer cells.
* Prominent Kupffer cells and increased hepatocyte polyploidy is LIVER CELL UNREST, common in people who are sick for a variety of reasons. Its diagnostic significance is nil.
* Future pathologists: You can stain the healthy canaliculi using your CEA stain.
You will learn about biopsying the liver (the open "wedge" biopsy, the classic through-the-skin cutting-neecle techniques, the tiny-pieces transjugular approach for the very-sick) on rotations (Gut 55: 1789, 2006). Lately, a liver cutting-needle biopsy has come to be considered "adequate" if it is 20 mm long and/or contains 11 or more complete portal tracts (Am. J. Clin. Path. 125: 710, 2006).
The Greek titan Prometheus had his liver devoured each day by a monster bird, but it always grew right back.
If individual hepatocytes are destroyed but the architecture of the lobule is NOT destroyed, the remaining hepatocytes will totally regenerate the liver parenchyma.
If whole lobules are destroyed, the remaining lobules will expand. They will function normally, though bile may not be drained quite so well.
Of course, if scar tissue alters the flow of blood through the liver (i.e., cirrhosis has occurred), regeneration will only produce less-than-fully-perfused nodules of liver cells. (This will disappoint well-read problem drinkers who understood that their hepatocytes had unlimited capacity to regenerate. )
* Liver biopsies are not always easy to read, especially if the community hospital pathologist isn't focused on liver. The value of a second opinion: Arch. Path. Lab. Med. 125: 736, 2001.
* Incredible as it may seem, your lecturer got his first exposure to pathology as freshman advisee of the dean of experimental liver pathology, Brown's Nelson Fausto, whose focus was and is liver regeneration. ("All right. You say you want to be a doctor. How serious are you?") Turned out to be a fantastic man and teacher. After years of bragging about this, I was delighted to see him as third author of the new "Big Robbins".
Increased bilirubin in the bloodstream is JAUNDICE.
There's no reason to review bilirubin production and metabolism here. You can check "Big Robbins" if you need refreshing.
Here's a simple review, similar to the one in "Big Robbins", of the various causes of jaundice:
TOO MUCH BILIRUBIN BEING PRODUCED ("hemolytic jaundice")
"Ineffective hematopoiesis", i.e., normoblasts dying in the bone marrow
Thalassemias (even mild ones like beta-thal minor)
Intravascular hemolysis (many, many reasons for this; IgG-mediated hemolysis of red cells is listed here as well though technically not "intravascular")
LIVER FAILS TO TAKE UP AND/OR CONJUGATE BILIRUBIN ("hepatocellular jaundice")
Hepatitis (many causes)
Cirrhosis (many causes)
Gilbert's non-disease and the Crigler-Najjar syndromes
NOTE: From "Biochemistry". Gilbert's (officially pronounced as French Zheeel-BEAR's) is a forme fruste of Crigler-Najjar (Lancet 346: 314, 1995; Lancet 345: 958, 1995). Both result from mutations of the glucuronyl transferase that solubilizes bilirubin. Crigler-Najjar (two subtypes) is always recessive, Gilbert's can be dominant (interference with normal function) or (more often) recessive (mild loss-of function alleles).
Gilbert's is extremely common (several % of the population) and usually a non-problem. One tipoff is that the bilirubin levels, which usually will stay below 6 mg/dL, increase during fasting. Some folks do find it troublesome. Gilbert's may be exacerbated by other illnesses or medications, in particular G6PD deficiency and/or the protease inhibitors used in anti-retroviral therapy (J. Inf. Dis. 192: 1381, 2005).
LIVER DOESN'T SEND BILIRUBIN TO THE RIGHT PLACE ("cholestatic jaundice")
Problems with the liver cells
Drugs (estrogen, anabolic steroids)
Dubin-Johnson (pigmented) non-disease
The hepatocytes are rich in a brown pigment (dPAS positive)
* These people lack a pump, which is coded by, of all things, the gene ABCC2 for the hated MRP2 multidrug-resistance protein (Gastroent.
For example, research suggests that HCA works by blocking a certain enzyme called adenosine triphosphate-citrate-lyase, which contributes to the formation of fat cells.
117: 653, 1999) that pumps cancer chemotherapy agents out of cancer cells.
* A specialist can diagnose Dubin-Johnson without biopsy by its effect on different urinary coproporphyrin levels. Don't worry about it.
Rotor (non-pigmented) non-disease.
* Making the call is easy because the liver refuses to take up the Tc 99 m-DIPA biliary scan radionuclide (Clin. Nuc. Med. 22: 635, 1997). Autosomal recessive; the gene awaits discovery..
* Byler's disease ("FIC-1/ATP8B1" and at least two other loci; familial intrahepatic cholestasis). This is a family of autosomal recessive illnesses in which there are problems with the bile transport proteins. There is a problem with bile transport in the liver, and sometimes "Byler bile" is appears coarsely granular. The Byler family from which all the index patients came is Amish and highly inbred; See Hepatology 26: 155, 1997. There is a Byler-like illness at BSEP, the bile salt export pump, and another at the multidrug-resistance protein 3 site).
"Benign familial recurrent intrahepatic cholestasis", the forme-fruste of Byler at FIC-1. Patients have intermittent cholestasis and elevated alkaline phosphatase. On biopsy during an attack, you will see bile in the canaliculi, and only in the canaliculi. Second locus Gastroent. 127: 379, 2004.
Really bad cases of other liver diseases (hepatitis, cirrhosis, alcoholism; i.e., when the liver fails, the picture is likely to be mixed).
Problems with the bile ducts in the liver
* Alagille's (dysmorphic child, intrahepatic bile ducts in the portal areas vanish over time; autosomal dominant, gene Jagged1 (Circulation 109: 1354, 2004, the variable liver disease itself Gut 49: 431, 2001; molecular biology Am. J. Path. 171: 641, 2007)
Normally, more than 70% of portal areas should contain a visible bile duct; if there are fewer than 50%, consider Alagille's.
Problems with the bile ducts beyond the liver (call a surgeon)
Gallstone in the common duct
Cancer (i.e., biliary, pancreatic, ampullary)
Traumatic / Iatrogenic (i.e., the surgeon nicked the common bile duct)
Note that in all but hemolytic jaundice, bile production will be diminished. Stools may become light-colored (gray if the bile is completely obstructed), and there will be diminished intestinal absorption of fat (pee-yew!) and fat-soluble vitamins.
Lab tests are of considerable help in distinguishing these entities.
Obviously, in the first two categories, the serum unconjugated bilirubin will be elevated.
In the third category, only the conjugated bilirubin will be elevated until the liver cells themselves are damaged. Serum BILE ACIDS ("bile salts") will also be increased from the onset, producing the troublesome itching seen in these syndromes. Conjugated (but not unconjugated) bilirubin in the bloodstream spills into the urine. You'll study other markers for cholestasis in the unit on lab testing.
On biopsy, obstructive jaundice presents the familiar BILE PLUGS, which begin as dilatations of the canaliculi and end up forming BILE LAKES when the canaliculi rupture.
* As the liver cells become damaged, they fill with soap bubbles (i.e., bile salts and water), producing FEATHERY DEGENERATION. You won't need to recognize this. Later, you'll see necrotic cells surrounding bile lakes.
WHEN THE LIVER FAILS
Regardless of cause, when the liver can no longer function as chemical plant, several unwholesome things happen.
JAUNDICE is usual. When the liver is really scrambled, hyperbilirubinemia is mostly the conjugated sort, i.e., the cells remember how to conjugate, but not what to do with, the bile. There is usually some unconjugated hyperbilirubinemia, too.
HYPOALBUMINEMIA is usual, since the liver isn't making albumin. Without albumin in the bloodstream, ascites and edema develop. By the way, HYPOCHOLESTEROLEMIA is usual in liver disease too (unless the primary problem is obstruction of bile flow -- why?), since the liver isn't producing LDL's. (This is part of the reason for the silly myth that "too low cholesterol is bad for you".)
COAGULOPATHY of liver disease (NEJM 365: 147, 2011) results from diminished hepatic synthesis of factors II, V, VII (first to go), IX, and X. (Note that absent vitamin K from malabsorption also prevents synthesis of II, VII, IX, and X.) Monitor all this by following the prothrombin times (rather than PTT, since factor VII is first to go and to return).
The anti-clotting factors are also diminished, and people talk about the clotting system in liver failure being "rebalanced".
Further, as the liver fails to clear factors that have become activated in the course of living, low-grade DIC is likely to develop. This is probably why PT and the classic measures correlate poorly with intractability of bleeding from varices / bleeding during liver transplantation.
As liver cells fail, detoxification of nasty compounds fails and HYPERAMMONEMIA and FETOR HEPATICUS (a distinctive mercaptan-based odor to the breath). Other side-effects are reddening of the thenar and hypothenar eminences ("palmar erythema"), spider "angiomas" (you'll learn about these in physical diagnosis), and (in men) gynecomastia and testicular atrophy. In longstanding liver failure, the parotid glands often enlarge for some reason (still completely unknown as of 2014).
THROMBOCYTOPENIA is due to lack of thrombopoietin: Am. J. Gast. 94: 1918, 1999.
HEPATORENAL SYNDROME is a syndrome of kidney failure.
We used to precipitate this by "lasixing" cirrhotics with ascites.
The pathophysiology, once obscure, is now clear. First, liver failure interferes with the breakdown of the vasodilator nitric oxide. Second, portal hypertension itself forces the splanchnic arteries to open wider at the expense of circulation to the rest of the body. Third, bacteria from the gut find their way into the mesenteric lymph nodes, where they cause all sorts of havoc with cytokines (NEJM 361: 1279, 2009). We now manage all but the worst cases by giving plasma expanders and vasopressin analogues (Gastroent. 122: 923, 2002) (to constrict the splanchnic circulation) plus dopamine (to open the renal microcirculation) helps (Hepatology 27: 35, 1998; Am. J. Gastroent. 92: 2113, 1997; Clin. Sci. 92: 433, 1997; Mayo. Clin. Proc. 71: 874, 1996; Lancet 362: 1819, 2003). When there is massive tense ascites, tapping and draining it ("large volume paracentesis") is helpful in the short-run. Unless the liver disease is reversible (i.e., alcoholic hepatitis or a drug allergy), this is just buying time while waiting for a liver transplant. Update South. Med. J. 103: 654, 2010.
- Type 1 hepatorenal syndrome is acute renal failure during a medical catastrophe, most often spontaneous bacterial peritonitis
HEPATOPULMONARY SYNDROME is seen when the liver fails. The small arterioles and capillaries of the lungs dilate preposterously causing V/Q mismatching (i.e., the oxygen cannot reach the centers of the vessels, and there are some shunts opening that bypass the alveoli altogether). There is no current remedy apart from curing the liver disease. See Gastroent 113: 606, 1997; Surg. Clin. N.A. 79: 23, 1999; Mayo Clin. Proc. 79: 42, 2004; Lancet 363: 1461, 2004 ("notoriously underdiagnosed"); NEJM 358: 2378, 2008; Med. Clin. N.A. 93: 871, 2009.
* One factor may be increased endothelin 1, either not cleared by the liver or actually manufactured in proliferating cholangiocytes (Dig. Dis. Sci. 57: 516, 2012).
* Future clinicians: In contrast to congestive heart failure, dyspnea in hepatopulmonary syndrome improves when lying flat ("platypnea"), since the V/Q mismatching is worst in the lung bases. Any idea why?
* Future clinicians: PORTOPULMONARY HYPERTENSION is the other lung problem caused by liver disease, and often coexists with hepatopulmonary syndrome. It's probably mediated by factors that aren't being cleared from the blood, and the histopathology is as for idiopathic pulmonary hypertension. Patients must have portal hypertension and/or bad liver disease, plus mean pulmonary arterial pressure above 25 mmHg at rest and a few other criteria. Update Hosp. Pract. 41(2): 62, April 2013.
HEPATIC ENCEPHALOPATHY is not a pretty sight, and probably results from a combination of factors, including nitrogen-containing false neurotransmitters (supposedly including octopamine -- remember that from "Biochemistry"? -- and some others) produced by the gut flora.
* Fatigue in liver failure may respond to ondansetron: Lancet 354: 397, 1999. The antibiotic rifaximin seems to help (NEJM 362: 1071, 2010).
Early in the process, there's a curious distortion of spatial perception. (The stereotype of accelerated confusion in the problem drinker is all too familiar -- he pours the whiskey onto his lap, rather than into the glass in his other hand; he cannot find his way home even when he sobers up. Whatever the cause, hepatic encephalopathy makes life far more difficult.) The first change on physical exam is ASTERIXIS, a curious flappy falling-asleep-and-waking-back-up of the fingers-hands-arms-whole body. Clinicians monitor hepatic encephalopathy by measuring blood ammonia.
<01383> Alzheimer II glia in hepatic encephalopathy (best one is in the center of the field; it appears as a swollen, pale nucleus)
In acute massive liver failure, cerebral edema is the pathway out of life in about 50% of cases (Lancet 351: 719, 1998). We're still making educated guesses about the mechanism.
When the liver finally gives up completely, REFRACTORY HYPOTENSION supervenes from total-body vascular relaxation (which we can suppose is due to the failure of the liver to metabolize some vasodilator, most likely one that's not yet been discovered.) Nothing you can do will save the patient.
Reminder: Serum liver enzyme (transaminases, lactate dehydrogenase) concentrations become elevated when liver cells are acutely injured. Note that in burned-out cirrhosis when drinking is stopped, liver enzymes will be normal.
Cirrhosis ("roaches of the liver", etc.) is scarring of the whole liver sufficient to permanently interfere with circulation of blood to the hepatocytes, no matter what the cause. You will see
NOTE: The development of fibrosis is still quite mysterious; we know the stellate cells are the ones responsible, but nobody really understands it or what we might do to stop it. Sometimes, you can see layer upon layer of reticulin fibers being laid down as liver cells die in waves; this is the sign of irreversible (?) damage in chronic hepatitis, and probably is how scars build up, at least in part.
<08846> cirrhosis, trichrome stain (fibrous tissue is blue, of course); micronodular
<39710> cirrhosis after hepatitis, gross photo showing uneven involvement of the liver lobules. Just recognize cirrhosis.
MICRONODULAR CIRRHOSIS: Most of the nodules are smaller than 0.3 cm, and the fibrous-scar bands are relatively thin.
Think of alcoholism, hemochromatosis (since alcohol and iron will involve all lobules equally), primary-autoimmune biliary cirrhosis (since portal areas tend to link to adjacent portal areas), or biliary infection/obstruction (same reason, "secondary biliary cirrhosis"; remember cystic fibrosis).
* The inborn errors of metabolism worth remembering are the bad kind of galactosemia, tyrosenemia, type IV glycogen storage disease, and hereditary fructose intolerance.
<08285> micronodular cirrhosis (this happens to have been a case of primary biliary cirrhosis); liver on left is normal
Urbana Atlas of Pathology
small nodular liver
Small liver with cirrhosis
Urbana Atlas of Pathology
MACRONODULAR CIRRHOSIS: Most of the nodules are larger than 0.3 cm, and the fibrous-scar bands are relatively thin.
Think of chronic hepatitis, with its uneven pattern of inflammation, progressed to cirrhosis (since viral disease is generally patchy and will not involve all lobules equally).
Wilson's disease, galactosemia, and alpha-1 antitrypsin deficiency may supposedly produce either pattern, though they probably begin involving lobules evenly; since they are accumulations and cell death releases the storage product, perhaps this explains the unevenness. As a matter of fact, a rehabilitated alcoholic's micronodular liver will, after a few years of sobriety, exhibit enough large regenerative nodules to qualify as macronodular.
* Pathologists only: "Incomplete septal cirrhosis" is stabilized (regressing?) macronodular cirrhosis with only thin fibrous bands and really no nodules. Liver function tests are better, but portal hypertension may be is more severe -- hence the tendency to say "cirrhosis" despite no nodules. See Gastroent. 106: 459, 1994.
* In an era in which regression of fibrosis is now well-recognized, just how useful the term "cirrhosis" is might be questioned (Am. J. Clin. Path. 137: 5, 2012). Your lecturer believes that the appearance of a cirrhotic liver is so distinctive that the term will always be with us. Please do remember that a diagnosis of "cirrhosis" is no longer a death sentence.
Necrosis and fibrosis
POST-NECROTIC CIRRHOSIS ("end-stage liver"): Macronodular cirrhosis with really big, thick fibrous-scar bands. Usually results either from submassive necrosis (i.e., whole lobules were destroyed), or (much more often) progression of another type of cirrhosis to the end stage (micronodular and macronodular no long mean anything as nodules coalesce).
<25659> macronodular cirrhosis (some big scars show progression to postnecrotic cirrhosis)
The traditional wisdom has been that the fibrosis in cirrhosis does not regress. Only recently have we begun to recognize that there may be regression, though not complete reversal, if the underlying process goes quiet.
Look for thin septa with holes in them, lone thick fibers (i.e., the surrounding thin stuff is gone), and other stuff that's harder to see why it means regression. See Arch. Path. Lab. Med. 124: 1599, 2000; update Hum. Path. 37: 1519, 2006 (the underlying problem must be corrected, and healing is incomplete and unpredictable, with only a minority showing convincing healing).
Especially in kids cured of thalassemia by marrow transplantation, extensive reversal of cirrhosis is now known to take place (Ann. Int. Med. 136: 667, 2002); there is often some regression when hepatitis C virus is eradicated from a long-time patient (Dig. Dis. Sci. 43: 2573, 1998; Ann. Int. Med. 149: 399, 2008); the new treatments for chronic hepatitis B cause a majority of patients with cirrhosis to revert to non-cirrhosis on histology (Lancet 381: 468, 2013), and when autoimmune hepatitis is controlled (Ann. Int. Med. 127: 981, 1997)
There are now animal models for stem cell work in partially-repairing the damaged liver (as is already in use for the damaged heart). Stay tuned: Gastroent. 135: 438, 2008.
* Death rates from cirrhosis (age-corrected) have run a curious pattern over the past 100 years. Between 1900 and 1934, deaths dropped by about 2/3; this coincided with the temperance movement and the massive decline in alcohol consumption. The end of Prohibition and the Great Depression resulted in a tremendous resurgence of alcohol overindulgence, and the rate of death from cirrhosis skyrocketed, peaking in 1970. Since then, they've dropped dramatically; I suspect the explanation is better nutrition and the recovery movement (Postgrad. Med. 115: 13, Jan 2004.)
CONGESTION of the liver receives excessive attention. There's no mystery; if the right side of the heart isn't pumping well enough, blood pools in the liver.
Except in the most sudden violent deaths, the central areas of the liver will be more or less congested. (If you're at an autopsy and someone asks, "Is that a nutmeg liver?", you can safely guess "Yes!")
Clinicians enjoy showing the hepatojugular reflux of those with congested livers, especially behind failing right ventricles. Pathologists enjoy exhibiting their cut nutmegs, which have light-and-dark areas that resemble congested liver.
* If you want to get fancy. instead of demonstrating hepatojugular reflux, you can now use a high-tech device to assess the "stiffness" of the liver, which is of course increased in the living when they have congestive heart failure in the absence of co-existing cirrhosis (Radiology 257: 872, 2010).
Someone really had fun
making this photo!
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office
If death has been preceded by a few hours of inadequate circulation (heart failure, shock), count on seeing some hepatocyte necrosis in the centers of lobules. (This is CENTRAL HEMORRHAGIC NECROSIS. Why the liver? Why in the centers? Think about it!)
This isn't "due to the congestion", but merely results from inadequate perfusion with oxygenated blood.
Clinicians may have noted "elevated liver transaminases" ("ISCHEMIC HEPATITIS"), and even mild jaundice. You can experience the transaminase elevations yourself by running a marathon. Don't worry, the liver will completely regenerate (since its connective tissue framework is still intact.)
If hepatic congestion and underperfusion have been extreme and longstanding, the rare CARDIAC SCLEROSIS may supervene. This is substantial fibrosis in the central areas of the lobule. (Grossly, the liver surface looks like a football, since scar contracts in the centers of the lobules.)
In extreme cases (i.e., tricuspid insufficiency, certain congenital heart surgeries), the fibrous tissue may bridge adjoining lobules -- true CARIAC CIRRHOSIS.
* That cardiac cirrhosis is real has recently been demonstrated by a study of people who have undergone the Fontan procedure, in which the right ventriclar pulse is transmitted directly to the hepatic veins. See J. Thorac. Card. Surg. 129: 1348, 2005.
* In cardiac cirrhosis, the central veins may become connected to one another, leaving "reverse lobulation", each with a single portal tract in the middle.
Otherwise, cardiac sclerosis is usually just an anatomic pathologist's curiosity.
The liver has a dual blood supply and, while hepatocytes are vulnerable to hypoxia, the stroma is very resistant and hepatocytes regenerate easily. This makes it difficult to truly arterially infarct the liver.
When a branch of the portal vein is compromised, the worst that usually happens is atrophy of hepatocytes in a region ("Zahn's infarct"; fresh lesions have much stasis of blood in the sinusoids and thus look blue).
HEPATIC VEIN THROMBOSIS ("Budd-Chiari")
<49262> Budd-Chiari; liver is engorged with blood and you can see the clots;
Sounds serious, and is. The most common cause is polycythemia vera. Most any other cause of hypercoagulable blood can produce "Budd-Chiari". Another important cause is invasion of the hepatic veins by hepatocellular carcinoma.
* We've long been puzzled by the link to polycythemia vera; now it seems that the JAK2 mutation that causes it is somehow key to these thrombi as well (Blood 117: 3968, 2011).
As you'd expect, in the acute case, the liver swells (ouch!), ascites develops rapidly, and the patient usually dies of venous infarction of the liver unless surgery or thrombolysis are performed.
In some foreign countries, "chronic Budd-Chiari" is a common problem. Nobody knows why. At autopsy, look for fibrous "webs" in the hepatic veins.
* Diabetic micro-angiopathy occasionally produces non-cirrhotic fibrosis (like hyaline arteriolar sclerosis) of the sinusoids. The entity is newly-named "diabetic hepatosclerosis" (Arch. Path. Lab. Med. 130: 27, 2006; update Am. J. Clin. Path. 132: 494, 2009). Probably it is common but under-recognized. Ordinarily the hepatic sinusoids have no basement membrane; if you see one, it's probably diabetic hepatosclerosis.
HEPATIC VENO-OCCLUSIVE DISEASE, clinically a Budd-Chiari mimic but with no thrombus, results from intimal thickening of the veins (onion-skinning, etc.). Think of Jamaican bush-tea (as in the lung: terrible health problem West. Ind. Med. J. 64: 60, 1997), comfrey, graft-vs.-host, radiation effect. Older review, emphasizing the "herbal tea" connection: Arch. Surg. 125: 525, 1990). Several high-power medications (sirolimus, thioguanine, oxaliplatin) have probably caused veno-occlusive disease. And it's one of the most serious complications of hematopoietic stem-cell transplantation (Lancet 379: 1301, 2012 -- * defibronate study).
Joel K. Greenson MD
* Sickle-cell patients often have chronic venous outflow obstruction (why?). Be careful about biopsying these people. Blood 101: 101, 2003.
PORTAL VEIN THROMBOSIS
Again, this is serious. It results from hypercoagulable blood, invasion by hepatocellular carcinoma, pancreatitis, or cirrhosis.
The major problems are ascites and venous infarction of the bowel.
NECROSIS OF THE LIVER
Infections tend to produce random areas of necrosis ("focal", "spotty"), ranging from tiny (most cases of viral hepatitis) to massive ("acute yellow atrophy" / "acute liver failure").
Poisons and other noxious things, on the other hand, tend to damage distinctive portions of the lobule (why?) More about this later.
CENTRAL NECROSIS: Ischemia, carbon tetrachloride, chloroform, acetaminophen
* Test-takers: Notice that all three of these famous poisons do their work by generating free radicals; perhaps this is rougher on the central areas because of the lower concentrations of oxygen found there. And please remember too that we usually see the livers of poisoning victims after they've been in shock -- which damages the central areas, anyway.
<07020> carbon tetrachloride, gross; note the necrosis (yellow, of course)
MIDZONAL NECROSIS: Yellow fever and dengue. (Think about why. It is in the virus's interest to have regenerating hepatocytes on both sides.)
PERIPHERAL NECROSIS: Acute iron poisoning (J. Tox. 39: 721, 2001), phosphorus, eclampsia/HELLP (in eclampsia/HELLP, fibrin microthrombi should be visible in the sinusoids near the portal areas).
<07023> liver showing phosphorus poisoning; note periportal necrosis
PELIOSIS HEPATIS ("blood cysts", a misnomer)
Lakes of blood among the hepatocytes. Usually a non-problem found on imaging or autopsy. On section, the liver features many easily visible holes filled with blood.
The pathology has recently been reviewed in depth (For. Sci. Int. 149: 25, 2005.)
Sometimes it is due to dilated veins ("phlebectatic peliosis"); in this case, the lesions are round and lined by endothelium and/or fibrosis, and the liver looks like swiss cheese.
In the more familiar sort of peliosis the lakes are lined only by hepatocytes ("parenchymal peliosis"); in this case, the lesions are irregularly-shaped.
Anabolic steroid use is the best-known cause (generally parenchymal), but many others are known (oral contraceptives, cachexia) or suspected (hemangiomas, congestion in people with mild weakness of the veins).
A blow to (or biopsy of) the involved organ may cause these to rupture, with serious hemorrhage.
VIRAL HEPATITIS: GENERAL CONSIDERATIONS
The hepatitis family is an alphabet-soup of viruses.
The good news is that Garcinia Extra does not lack in this department.
Any inquiries concerning health, product information or advice seeking are welcome.
However, the anatomic pathology is generally similar. Some viruses are better at producing different patterns than are others.
You can get each of these infections only once. But B can linger, and C usually does linger, as a minor or major problem.
As with most viral diseases, infectivity peaks just before symptoms appear. Acute hepatitis is heralded by the blahs. As the immune system gears up, joint pains and rash can occur. Appetite vanishes, and the patient typically becomes utterly revolted by tobacco. (Smoking cessation is a redeeming feature of the acute hepatitis family.)
In the acute disease, the liver swells and becomes tender, jaundice often appears (mild cases are "anicteric"), and (with influx of bile into the bloodstream) the patient starts to itch and to pass brown urine (why?) Serum transaminases go sky-high, and other lab evidence of liver disease may become apparent.
The best treatment your lecturer knows for the acute phase is masterful inactivity for all but C, intensive therapy for C. Educate the patient, find out who else needs to be checked for hepatitis or get prophylactic gamma globulin, and give clotting factors if you must.
ACUTE VIRAL HEPATITIS: You will see
Note that in hepatitis, the cells may die either by lysis or apoptosis, or both. Probably the lysis is due to the viruses and/or to antibodies, while the apoptosis is caused by instructions to self-destruct delivered by the T-cells.
<05961> acute viral hepatitis with Councilman body
<08834> acute viral hepatitis; sinusoids are not visible, lots of inflammatory cells
<11787> acute viral hepatitis, great bile plugging
<12770> acute viral hepatitis (do you see a Councilman body?)
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Necrosis and lobular collapse
MASSIVE NECROSIS ("FULMINANT HEPATITIS"; "ACUTE YELLOW ATROPHY") may supervene on any kind of acute hepatitis, and often kills the patient in short order. Update Lancet 376: 190, 2010.
Causes range from medicines (idiosyndratic responses to real medicines; adulterants in quack medicines, really bad hepatitis B, D, or E; mushroom poisoning; rare complications of pregnancy; the worst cases of typhoid; extreme vascular disease; rarely hepatitis A, maybe not hepatitis C)
Grossly, as you would expect, the liver is shrunken, red-to-yellow, soft, and flabby, with a wrinkled capsule.
Histologically, the hepatocytes are almost all gone (lytic necrosis and/or apoptosis), leaving a collapsed fibrous tissue framework. Don't expect to see much inflammation.
SUB-MASSIVE NECROSIS is a little less striking histologically and lasts a little longer, killing the patient in a few months. (Or the patient may recover after being super-sick for a few months.)
If a patient survives either process, the parenchyma is usually intact, and recovery should be complete, without cirrhosis. Rarely, the collapsed reticulin meshwork of the liver turns into broad scars (instant "post-necrotic cirrhosis").
<13320> massive necrosis after hepatitis, gross (nothing left but the reticulin and endothelial framework!)
<13321> massive necrosis after hepatitis, histology
<13322> massive necrosis after hepatitis, histology
Pittsburgh Pathology Cases
CHRONIC HEPATITIS: Inflammation of the liver for more than six months.
You will see a dense, mostly-lymphocytic inflammatory infiltrate in the portal areas, with or without spill-over into the parenchyma.
There may be some smoldering changes resembling acute hepatitis in the parenchyma.
In mild cases, the limiting plate is intact (i.e., there is no interface hepatitis). We used to call this "chronic persistent hepatitis".
<12788> mild chronic hepatitis, reticulin stain (see the limiting plate intact); you don't need to tell this isn't normal liver;
<12791> mild chronic hepatitis, trichrome (again, see the limiting plate intact); again, you can't tell this isn't normal liver;
These findings are more ominous when the patient has chronic hepatitis clinically:
Drug-induced liver disease (most notably methotrexate), Wilson's, alpha-1 antitrypsin deficiency, and the autoimmune "lupoid" hepatitis family also typically pass through a "chronic active hepatitis" histopathology stage on their way to cirrhosis.
<12800> severe chronic hepatitis, piecemeal necrosis
<20328> severe chronic hepatitis; almost to cirrhosis (the nodules are not yet completely separate)
<40279> severe chronic hepatitis, note the necrotic cells
<20183> severe chronic hepatitis with good bridging necrosis; the hepatocytes are stained orange and the bridge is an area of lytic necrosis
Joel K. Greenson MD
Future pathologists please note: Any and all of these patterns (from acute hepatitis to post-necrotic cirrhosis) can be mimicked by idiosyncratic reactions to various drugs. Chronic hepatitis and its sequelae are often caused by autoimmunity.
HEPATITIS A ("infectious hepatitis")
This is an unpleasant but almost always self-limited disease caused by a tiny RNA enterovirus (* picornavirus; "pico-" means "tiny", and "rna" you can figure out).
Hepatitis A is transmitted by the fecal-oral route, i.e., poor sanitation, small kids (i.e., day-care or institutions), hands (J. Clin. Micro. 30: 757, 1992, note that there are countries where toilet paper isn't used), raw oysters (be sure to ask), some gay male sexual practices (JAMA 267: 1587, 1992), others. Hepatitis A is more common overseas but is no rarity in the U.S.
Hepatitis A, until recently an endemic scourge on many Indian reservations (MMWR 46: 600, 1997) has become much less common thanks to the recommendation to immunize all these children (Am. J. Pub. Health 94: 996, 2004).
* The 1998 strawberry outbreak: NEJM 340: 595, 1999.
The incubation period is about two weeks, and this is the time when virus is shed in the feces. The infection in kids is usually asymptomatic. Adults who get symptoms at all suffer jaundice and discomfort for a few weeks. Once in a while, the disease is fatal.
You'll hear different versions of whether the virus itself damages hepatocytes (the other enteroviruses are cytotoxic), or whether the liver damage is actually wrought by the body's immune response.
Immune response is exactly what you'd expect:
IgM ANTI-HAV appears in the blood when the symptoms begin, clears the infection (which may wax and wane clinically for a few months), and usually disappears within 12 months.
Actually, IgM often sticks around indefinitely. Don't draw any conclusions from its presence if the person's not sick (Arch. Path. Lab. Med. 137: 90, 2013).
IgG ANTI-HAV appears in the blood during the symptomatic period, and usually stays around for life, rendering the patient immune.
Occasionally the disease causes acute yellow atrophy and death/transplantation (Am. J. Gastro. 98: 448, 2003).
Hepatitis A very seldom becomes chronic or leads directly to cirrhosis. There is probably no carrier state. At worst, the disease might be a trigger for autoimmune chronic hepatitis, but the virus won't stay around.
* How the vaccine came about: Lancet 343: 321 & 322, 1994; J. Inf. Dis. 169: 996, 1994; JAMA 271: 1328, 1994; JAMA 273: 906, 1995 (now classic). Hepatitis A vaccine for post-exposure prophylaxis seems to work about as well as immune globulin: NEJM 357: 1685, 2007.
HEPATITIS B ("serum hepatitis"; update NEJM 359: 1486, 2008; Lancet 373: 582, 2009)
The world's most serious DNA-virus-related health problem. The reservoir for the virus ("HBV", "Dane particle") is the world's 300 million (Proc. Nat. Acad. Sci. 93: 6542, 1996) or 350 million (WHO 2009) or 400 million (ASCP) carriers, most of whom are asymptomatic and probably have histologically normal or near-normal livers.
Perhaps one person in three worldwide has met the hepatitis B virus; most people cure themselves.
<10532> hepatitis B, * orcein stain (stains the virus)
<11708> hepatitis B, core antigen stained in nuclei
Even an infinitesimal amount of infected blood, when introduced into another person's tissues, is highly effective in transmitting the infection.
- transfusions (of course, we check donor units)
People born uninfected in the poor nations also frequently turn positive during their childhood. This has been blamed on bedbugs; probably this isn't the main problem (Lancet 343: 761, 1994).
In the U.S. underclass, infection is also rampant, with around 25% of forensic-service deaths being core-antibody positive (J. For. Sci. 38: 1075, 1993).
* Hepatitis B immunization has resulted in a triumphant reduction in the prevalence of carriage in Taiwan and the rate of hepatocellular carcinomas (JAMA 276: 906, 1996).
* In 1997, I predicted the 1998-9 media hype that the vaccine causes multiple sclerosis. The activists don't have the numbers, but even after the claim was already totally discredited, many lawsuits still got filed (Science 281: 630, 1998).
* Catching hepatitis B from the surgeon, even when e-antigen-negative ("low-risk"): NEJM 336: 178, 1997.
HBsAg ("Australia antigen"): Surface antigen. Envelope protein. During the productive infection, the liver cells make considerable excess non-infectious HBsAg, facilitating diagnosis.
HBcAg: Core antigen. Nucleocapsid.
* Not surprisingly, several genetic variants exist, which affect both the progress of the hepatitis, and the prognosis of any hepatocellular carcinomas that arise here. This will affect you by the time you are in practice. See Gastroent. 137: 1687, 2009.
HBeAg: Another nucleocapsid antigen, which means the virus is being replicated.
* Interestingly, entry of the virus into the hepatocyte is by means of binding to polymerized serum albumin.
After a person first meets the virus, the incubation period is usually 1-4 months.
Antigens and antibodies:
HBsAg first appears in the blood shortly before symptoms begin (if they are to begin -- maybe 70% of infections are asymptomatic). It remains in the blood for the duration of the infection, whether it is acutely symptomatic, slowly-progressive / subclinical, or merely the carrier state.
HBeAg appears in the blood just after HBsAg, and before symptoms start. It remains as long as there is acute viral replication (you're VERY contagious. ), and disappears if (and only if) viral replication stops. The patient is still sick when HBeAg disappears, but can take comfort in the good news.
Anti-HBeAg appears soon after viral replication and HBeAg production stop (if they stop). The patient can still be sick, but this is another piece of good news.
If HBeAb stays around, it's a marker for the person being very contagious -- bad enough that the NCAA forbids sports participation for a chronic carrier.
Don't ask for an assay of HBcAg, the core antigen in the blood. It's an intranuclear protein and there's almost none in the blood. However, Anti-HBcAg, in its IgM form, appears in the blood typically before symptoms begin, and generally remains present for years (IgG anti-HBcAg will eventually take over, maybe). If a person with clinical hepatitis has cleared his blood of HBsAg, but has not yet developed detectable anti-HBsAg, the presence of IgM anti-HBcAg confirms that the infection is, indeed, hepatitis B and is in the CORE WINDOW.
Anti-HBsAg is generally present when the infection is pretty much over, and is a good sign of recovery.
NOTE: Now that we use viral DNA to discover hepatitis B infection, we're discovering quite a few folks who never mount an antibody response. These folks seem to fail to expand their clone of HBV-specific T-cells (Gastroent 134: 1470, 2008).
"Occult hepatitis B" has undetectable HBsAg, positve anti-HBc, and positive anti-HBs, but there's sometimes viral DNA detectable in the blood, and the virus is still hiding in the liver. Its true frequency is of course unknown. These people will have the disease flare when they get immunosuppressed by chemotherapy, infamously by rituximab. Overall, about 1/3 of patients who are HBsAg-positive will reactivate (i.e., the virus reappears in the blood), and of these, maybe a quarter will get very sick, especially if they were not given lamivudine to prevent it. People with occult infection (i.e, anti-HBs negative, anti-HBc positive) may serorevert (HBsAg reappears in the blood) during chemotherapy.
BEWARE! During the time between disappearance of HBsAg and appearance of anti-HBsAg, the patient may experience a potentially-lethal type III systemic vasculitis. (Why?)
If your patient is anti-HBsAg positive and anti-HBcAg negative, probably this person has had the hepatitis B vaccine (why?)
* Well, maybe it's not a SURE sign of recovery; the Scripps crew has found viral DNA up to five years after appearance of the antibody, but the patients don't seem sick or catching (J. Clin. Inv. 93: 230, 1994).
Symptoms begin in hepatitis B infection only when T-cells become angry with HBsAg and HBcAg and start killing the hepatocytes that produce them. Histopathologists find T-cytotoxic cells where the hepatocytes are dying. Eventually, the only surviving liver cells are the ones that won't continue making viruses, and these replenish the liver.
The acute disease may be subclinical, or can cause weeks of jaundice and misery, or can cause fulminant hepatitis and death (this used to kill a few percent of patients with acute hepatitis B before we had effective antiviral medications), or sub-massive hepatic necrosis with resolution or cirrhosis.
Survivors (and 99% of people survive the acute episode) usually clear themselves of the virus, but maybe 10% fail to do so. These can become healthy carriers, develop chronic hepatitis that may remit or progress to cirrhosis if untreated. Rule of thumb: The more severe the initial illness, the less chance of remaining chronically infected (why?) Terminology: Chronic hepatitis B means HBsAg has been present in the bloodstream for 6 months or more.
NOTE: Carrying hepatitis B, with or without ongoing liver disease, is an important cause of cryoglobulinemia and/or "polyarteritis nodosa of hepatitis B" (both immune complex, type III immune injury problems).
NOTE: People who become carriers are those who mount a poor immune response. Men (weaker immune response) are more at risk than women; different HLA types differ in susceptibility (Lancet 344: 1194, 1994).
NOTE: Quite a few patients with hepatitis B in the blood but persistently normal transaminases do indeed go on to fibrosis and cirrhosis (Gastroent. 134: 1376, 2008).
Further, anyone who carries around the virus for a long time is at substantial risk for hepatocellular carcinoma. (Hepatitis B and/or hepatitis C contribute to most cases of this cancer, which worldwide is one of the most common fatal diseases. In the case of hepatitis B, the virus may be acting as a mitogen that allows Nowell's law to act, and/or mutating genes at or near its insertion sites: J. Virol. 65: 6761, 1991; there is no doubt that insertion of the virus can and does scramble chromosomes: Proc. Nat. Acad. Sci. 88: 9248, 1991.)
People who continue to harbor the virus are probably those that are not especially good at making interferon (the chronically sick, the immunocompromised, little kids, the unlucky, men much more often than women). Alpha-interferon was the original the mainstay of therapy for chronic hepatitis B infections, and the results are encouraging, with maybe half of people going into remission. Of course, interferon therapy was expensive and produces 'flu-like symptoms, but it was better than dying or infecting your spouse. And thankfully the risk for hepatocellular carcinoma also dropped greatly (Cancer 66: 2395, 1990 was the first big one).
Future histopathologists: You can stain for HBsAg in the cytoplasm, or core antigen in the nucleus. "GROUND GLASS HEPATOCYTES", with greatly increased smooth endoplasmic reticulum suggest chronic hepatitis B infection.
* Don't worry about the "sanded nuclei", full of core antigen, that are classically described in hepatitis B. This is subtle and of no use clinically, and we won't ask you to recognize them.
We may hope that the hepatitis B vaccine will eventually make this infection, and its dread sequelae, a thing of the past. Gambia institutes HBV vaccination of its population (Lancet 341: 1129, 1993). Kids in the U.S. should get immunized, too (Pediatrics 93: 747, 1994). Please be sure you, too, are immune, Doc.
A few mutant viruses that can affect the immunized are now appearing (Epid. & Inf. 124: 295, 2000).
HEPATITIS D (Lancet 378: 73, 2011)
"Delta hepatitis virus" (HDV) is an incomplete RNA virus that can replicate only while synthesis of HBsAg is also taking place. Unlike HBV, delta is directly cytopathic to hepatocytes. About 15 million people are infected worldwide.
Delta may CO-INFECT (i.e., arrive under a person's skin at the same time as the HBV particle) or SUPERINFECT (i.e., arrive under the skin of a person already infected with HBV). Fortunately, delta is relatively hard to transmit (somewhere between HBV and HIV in infectivity), and hepatitis D is most common in gay men and (in the developed world, especially ) IV-drug-abusers.
The results are grim. In co-infections, fulminant disease is common (maybe 5%). In a superinfection, the victim experiences a second round of acute hepatitis, which tends (maybe 50% of the time) to turn chronic and progressive. Treating chronic hepatitis D with alpha-IF: NEJM 330: 88, 1994 (it helps around half of them while being treated; half of these relapse.) If the virus continues replicating, death is near-certain after a few decades (Gastroenterology 136: 1629, 2009).
Fortunately, carriers of delta are probably uncommon. Delta kills maybe 1000 people a year in the USA.
* Disturbingly, there's a fair amount of hepatitis D in school children in Mongolia, and it seems to be acquired through dirty needles in the health care setting (Am. J. Trop. Med. Hyg. 75: 365, 2006).
* LABREA HEPATITIS, noted in the western parts of the Amazon region, is a fulminant, deadly hepatitis of children and young adults caused by hepatitis B and D. There is microvesicular steatosis, and inflammation of the portal and central veins, and "morula cells", macrophages loaded with virus (Trans. Royal Soc. Trop. Med. 101: 831, 2007).
HEPATITIS C (the vast majority of the old non-A, non-B hepatitis cases) updates Ann. Int. Med. 132: 296, 2000; Mayo Clin. Proc. 73: 355, 1998; Lancet 362: 2095, 2003.
This flavivirus (HCV) and its related disease spectrum are now well-characterized. Worldwide, about 170 million people carry the virus (Gut 58: 846, 2009). In the U.S., 1% of asymptomatic people are positive for HCV (maybe more than this among swingers and MUCH more among IV drug users; maybe 0.3% in those not in these risk groups; health care workers aren't at increased risk: Lancet 343: 1618, 1994; ear-piercing is a risk factor: NEJM 334: 1691, 1996; 19% positive for inner-city forensic-pathology service deaths J. For. Sci. 38: 1075, 1993); in the 2000's, intravenous drug use was the most common cause in the USA, with 98% of junkies positive in some communities; in the poor nations, it's around 5%; worldwide 3%; the highest known prevalence is around 20% in Egypt (see below). At least 170 million people are infected worldwide (Science 288: 339, 2000), at least 3 million in the USA, with about 10000 deaths yearly (that mortality figure is conservative and is going to increase: JAMA 297: 784, 2007).
Hepatitis C virus is transmitted by the same routes as hepatitis B, but is clearly not nearly so catching. The best route seems to be blood transfusion or needle-sharing (J. Inf. Dis. 162: 823, 1990; hemophiliacs Blood 84: 1020, 1994).
Needlesticks from infected blood carry about a 6% chance of infection (Br. Med. J. 315: 333, 1997) and prophylactic treatment with anti-hepatitis C medicines is now administered routinely after such events.
Strangely, nobody yet knows the prevalence of perinatally-transmitted hepatitis C, but it can declare itself later in life as a fulminant illness: Arch. Dis. Child. 88: 160, 2003.
Thankfully, with changing lifestyles (maybe) and surveillance in the hospital (certainly), the transmission rate of hepatitis C is only about 1/5 what it was in the 1980's (Sci. Am. 280(3): 17, March 1999.)
The risk from a transfusion is now about 1 in 2 million (Lancet 361: 161, 2003).
* Among several hundred Irish women infected in the '70's by bad RhoGam, half still had demonstrable virus, most of these had some inflammation, many had some fibrosis, but only two had cirrhosis (NEJM 340: 1228, 1999).
Hepatitis C transmission by acupuncture is now so well-known that you'd do well to warn your patients to be sure they know who's doing it (Can. Fam. Phys. 49: 985, 2003).
Sexual transmission is very rare but it probably occurs (JAMA 269: 361 and 392, 1993; Gut 45: 7, 1999; the risk to MSM's seems very low Am. J. Pub. Health 95: 502, 2005); older studies suggest that around a quarter of spouses do eventually catch it (Ann.
Some of the subjects took HCA, while others took a placebo.
Int. Med. 120: 748, 1994). Vertical transmission from Mom is common, especially if Mom has lots of virus on board: NEJM 330: 744, 1994. In some communities -- in striking contrast to HIV, hepatitis B, and so forth -- around 40% of people who carry the virus haven't got a clue how they got it.
* Maybe from the barber (?! the macho man's horror; see Lancet 345: 658, 1995). Nothing further.
In the US, if you're living clean enough to donate blood, your chance of coming down with hepatitis C is very low (BMJ 316: 1413, 1998; NEJM 341: 556, 1999).
A majority of people with the antibody do have detectable virus by PCR in the blood.
* Unlike hepatitis B and D, to date there is no reliable stain for hepatitis C.
The presence of the virus's RNA in the blood (or liver tissue, which is harder to obtain) is today's standard for proving infection. The exact specificity of a positive antibody depends on the test (the cheap first-generation assays were infamously nonspecific) and of course the population screened (clean-living people's positive screens are more likely to be false than needle-drug-user's positive screens). For an update on the difficult subject of who to screen and how, see Am. J. Gastro. 100: 607, 2005.
We used to teach that only a few folks do clear the virus quickly after being infected (Science 288: 333, 2000); with newer methods of detecting acute infection, some folks say that around 67% clear themselves without treatment within 8 weeks (Hepatology 37: 60, 2003), though it's also known that many people's viral levels simply become undetectable and the infection does recur. There's still a question of whether to treat immediately or wait-and-see. And some people who are chronically infected have viremia only intermittently, and in some studies, rates of spontaneous clearance over the years are relatively high (Irish J. Med. Sci. 174: 37, 2005 gives a surprising 31%, perhaps just the luck o' the Irish.)
* Children exposed from blood transfusion do much better, often clearing themselves (NEJM 341: 912, 1999).
Egypt, with around 20% of its people infected, has the highest rate. Probably because of needles (used to administer antimony in the treatment of schistosomiasis ) not being sterilized between patients during one of the aggressive "eradicate schistosomiasis" campaigns (Lancet 355: 887, 2000).
Incubation period is a week to six months; texts give the average as 8 weeks. The acute infection is more likely to be subclinical (or cause minor "belly trouble"), and massive necrosis does not occur. However, infection usually becomes progressive. Nobody knows the rate of subclinical infections, so nobody truly knows how many people clear themselves of the infection in the acute phase. If you don't clear it, fortunately, progression is slow, and severe liver failure results in only about 10-30% of people and usually only after decades.
* Miraversin, an antisense oligonucleotide for hepatitis C (miravirsen): NEJM 368: 1685, 2013.
You can get sick several times if you get a big dose of the bug several times (Lancet 343: 388, 1994). After acquiring the virus via blood transfusion, chronic infection with abnormal liver histology happens more often than not (Ann. Int. Med. 137: 961, 2002). The impact on overall length of life is usually small (NEJM 327: 1906, 1992; Gut 47: 845, 2000) but the infection is still a serious business. Patients who are treated for their illness cost third-party payers much less than those who do not (lost productivity, advanced disease): Dig. Dis. Sci. 57: 2995, 2012.
Around a third of hepatitis C virus carriers have aggressive-looking chronic hepatitis or cirrhosis (Br. Med. J. 308: 695, 1994). Unlike the other viral diseases, there is often quite a bit of fatty change (correlates with severity: J. Inf. Dis. 192: 1943, 2005 -- some strains produce random fat-laden cells, others cause the metabolic syndrome itself with most cells in zone 3) and/or regenerative change in the bile ducts, rather few inflammatory cells (maybe just lymphoid aggregates) in the parenchyma, and a portal infiltrate that's all lymphocytes (no plasma cells or eosinophils, and perhaps even making a "nice lymphoid aggregate" or even a "nice lymphoid follicle / germinal center") suggests hepatitis C. The progression to fibrosis is steady and usually takes decades; if you're male, a drinker, older, and/or unlucky, it may take only a decade or so (Lancet 349: 825, 1997.)
NOTE: As with hepatitis B, carrying hepatitis C, with or without ongoing liver disease, is an important cause of cryoglobulinemia (Am. J. Med. 96: 124, 1994; NEJM 330: 751, 1994 for the success of alpha-IF therapy). The cryoglobulins are immune complexes made of the virus and the antibodies.
* How does hepatitis C virus produce fibrosis? There is often remarkably little inflammation. In one model, the virally-infected hepatocytes produce huge amounts of transforming growth factor beta, causing stellate cells to produce collagen. Stay tuned; this may become the basis for a novel anti-fibrogenic therapy (Gastroenterology 129: 246, 2005).
* NOTE: Hepatitis C virus tends to drive out hepatitis B virus over the long-term in patients infected with both (Gastroent. 106: 1048, 1994, others).
* As with hepatiis B, quite a few of these people never have elevated transaminases, even as they progress to cirrhosis. We have to wonder how these people's infections were detected (Am. J. Gastro. 98: 1588, 2003).
We now eliminate about half of chronic infections using a combination of pegylated interferon and ribavirin. This is one of the most important triumphs of late-20th_century medicine in the last decade. More about this on your gastroenterology rotation.
* Future pathologists only:
Metavir fibrosis score:
F1 = portal fibrosis, no septa
F2 = portal fibrosas, a few septa
F3 = portal fibrosis, lots of septa, no cirrhosis
A1 = mild activity
A2 = moderate activity
A3 = severe activity
Ishak fibrosis score:
0 = no fibrosis 1-2 = portal fibrosis, no bridging 3-4 = bridging, no cirrhosis 5-6 = cirrhosis
For the harder-to-treat HCV genotypes, a metavir score of F2 or less (few or no septa) or a Ishak score of 2 or less (no bridging) may justify following but not treating the patient.
Like hepatitis B, longstanding infection with hepatitis C places a person at grave risk for hepatocellular carcinoma (Lancet 345: 413, 1995).
Nowadays, hepatitis&C infections are treated aggressively with the hope of cure. The difficult genotype 1 seems to respond well to the regimen with added boceprevir (NEJM 364: 1195 & 1207, 2011 -- now there are reports of most patients having their infections cleared with ABT-450 -- protease inhibitor -- plus retonavir NEJM 370: 222, 2014). For people with genotypes 1, 2 or 3 even with previous treatment failures, the combination of daclatasvir and sofobuvir seems to clear most infections NEJM 370: 211, 2014. Ledipasvir and sofosbuvir: NEJM 370: 1483, 1879 & 1889, 2014. Ombitasvir, dasabuvir and ribavirin: NEJM 270: 1594 and 1604, 2014. Oral regimen: Daclatasvir, asunaprevir, and beclabuvir: JAMA 313: 1728, 2015. More about the emerging regimens, which can work even for the hard-to-treat genetype 1 strain: Lancet 385: 1107, 2015. You can read about a variety of other current studies.
* Transgenic mice carrying only the core protein develop steatosis, adenomas, and then hepatocellular carcinomas (Nat. Med. 4: 1065, 1998).
In contrast to hepatitis B, the presence of ANTI-HCV usually indicates the persistent presence of hepatitis C virus in the body. The original work found that around 60% of people found to be positive with the first-generation antibody assay did indeed have virus detectable by PCR. The newer assays (RIBA) are much more specific, and are used if the screening is positive but no virus is present in the blood -- if these are positive, the person has probably self-cured.
* There's hope that we'll have a hepatitis C vaccine, but it's a long way off. Like HIV, the virus is notorious for mutating rapidly, even in the same patient, and this isn't good for vaccine-makers. And like HIV, antibodies aren't very protective. Updates J. Imm. 176: 6065, 2006; Gastroenterology 130: 453, 2006.
HEPATITIS G and the HEPATITIS GC family are hepatitis-C-like flaviviruses.
Hepatitis G virus and its cousin GB virus C are relatively common infectious agents that produces a chronic viremia. They're now considered two isolates of the same virus "GB Virus C". They are known to be transmitted by blood products, sex, needles, and mother-to-child (Arch. Dis. Child. 80: F72, 1999). There's an antibody test (Lancet 349: 318, 1997).
Whether these critters ever make anybody sick has been under study for two decades There doesn't seem to be an acute illness (NEJM 336: 741 & 747, 1997). More studies failing to show any evidence that they make you sick: Gut 103: 103, 1998; Arch. Dis. Child. 80: F72, 1999; Ann. Int. Med. 126: 874, 1997.
A person may clear the virus, or have persistent virus infection. Around 85% of hepatitis C patients have evidence of past or present infection (J. Inf. Dis. 194: 410, 2006).
The virus also multiplies in B- and T-lymphocytes (J. Inf. Dis. 193: 451, 2006). It inhibits HIV replication in vitro (J. Inf. Dis. 192: 2147, 2005; Lancet 363: 2040, 2004), and it is claimed that persistent GB virus C coinfection slows the rate of progression of HIV disease (J. Inf. Dis. 194: 410, 2006; NEJM 350: 981, 2004), Stay tuned.
* People who study these things say that C, G, and the GC's all evolved from yellow fever or dengue fairly recently.
* TTV ("transfusion transmitted virus") is a DNA virus that's very common (10% of folks) in Japan, less common in the West. It elevates transaminases after a transfusion, but nobody's found anyone sick from it yet (Lancet 352: 164, 1998).
HEPATITIS E: An important, epidemic calicivirus (now hepevirus) infection in the poor nations (Lancet 379: 2477, 2012; NEJM 367: 1237, 2012).
* This disease produced at least one major outbreak (New Delhi monsoon floods, 1955) but was officially discovered when it caused an outbreak at a Soviet military camp in Afghanistan in 1983. Dr. Mikhail S. Balayan, who knew he was immune to hepatitis A, mixed "a pooled faecal extract from affected soldiers" with his yogurt, went back to Moscow, and when he got sick found the new virus (named HEV) in his stool by electron microscopy Dr. Balayan won the Order of Lenin.
It's usually mild, but there are around 70,000 deaths worldwide each year from massive hepatic necrosis. For some reason, pregnant women (or those taking oral contraceptives: Am. J. Trop. Med. 82: 12, 2010) are likely to be severely affected, and may die. It never becomes chronic in healthy folks. There is no specific treatment. In outbreaks, mortality can be as high as 25%.
In the poor nations, it's waterborne. The developed world has different strains and probably these are from contaminated, poorly-cooked meat. In 2009, the fact that this infection is fairly common in France was linked to the practice of eating raw pig livers. I am not making this up (Emerg. Inf. Dis. 15: 110, 2009).
You'll make the diagnosis on the presence of IgM antibodies. Around 25% of people from the Middle East have had it, but it is less prevalent in the rest of the world (J. Inf. Dis. 16: 801, 1994). Review from the CDC in Inf. Dis. Clin. N.A. 14: 669, 2000.
The first cases of chronic hepatitis E, progressing to cirrhosis, were reported in transplant recipients in 2008 (NEJM 358: 811 & 859, 2008).
Vaccine NEJM 356: 895, 2007; Lancet 376: 849, 2010; NEJM 372: 899 & 914, 2015.
YELLOW FEVER: The reservoir is monkeys (South America and Africa) and it is transmitted monkey-to-human or human-to-human by the Aedes mosquito. The diagnosis is clinical. A relatively mild febrile illness with viremia lasts 3-6 days; in a minority, a fulminant hepatitis follows after initial remission. Pathologists see Councilman bodies, necrosis especially in the mid-zone of the lobule, and a surprising lack of inflammatory response (still the pattern: Trans. Royal. Soc. Trop. Med. 101: 831, 2007). Yellow fever today in Bolivia: Lancet 353: 1558, 1999. Death from yellow fever is probably not so much due to liver failure as to overactivation of cytokines, much as in sepsis: J. Inf. Dis. 190: 1821, 2004. The live yellow-fever vaccine is one of the oldest and most effective but kills some of the recipients; a new inactivated vaccine shows promise (NEJM 364: 1326, 2011). Yellow fever outbreak in the Darfur region of the Sudan: NEJM 368: 689, 2013.
CHRONIC HEPATITIS NOT CAUSED BY VIRUSES
AUTOIMMUNE ("lupoid"; "plasmacytic") HEPATITIS: Chronic hepatitis progressing to cirrhosis, without chronic virus infection but with evidence of immune injury. Reviews NEJM 354: 54, 2006; Lancet 382: 1433, 2013.
Poorly understood, but fairly common (prevalence of around 16 people in 100,000, much higher in some groups especially the Eskimo / Inuit), and deadly if missed (3/4 dead in ten years if untreated). We'll distinguish the different types (which bear little relationship to real lupus) when we discuss liver function testing. The most common type ("type I") features autoantibodies against smooth muscle / filamentous actin / F-actin. Other types are distinguished by other antibodies (anti-LKM-1 for the much more severe type II; anti-SLA/soluble liver antigen/LP/liver-pancreas once defined "type III" but now are a variant of type I: Gastroent. 135: 2107, 2008), but the havoc is wrought by the T-cells.
* Despite its reputation as a slow, chronic illness, it may be acute and even fulminant (Dig. Dis. Sci. 58: 897, 2013).
* Leave the diagnosis of the uncommon "autoantibody-negative autoimmune hepatitis" to the gastroenterologists. There may be an unknown autoantigen, or the familiar antibodies may show up later (Dig. Dis. Sci. 57: 610, 2012).
Current thinking is that something first damages the liver (probably one of the viral hepatitis family, or some drug or poison, or whatever), and patients then get sensitized to their livers and start destroying them over the long haul. More about this later.
Drugs that trigger "lupoid hepatitis" include some of the older ones, and today minocycline (Br. Med. J. 312: 169, 1996) and the infamous herbal remedy "dai-taiko-so".
Future pathologists: Autoimmune chronic hepatitis usually features a lot more plasma cells than does viral chronic hepatitis.
* F-actin antibodies plus a histologic picture of autoimmune plasmacytic hepatitis is fairly common in chronic hepatitis C infection and HCV/HIV coinfection (Am. J. Clin. Path. 314: 228, 2012). If you are serious about this being autoimmune hepatitis, ask for the ELISA (very sensitive, now will perhaps define the disease) rather than immunofluorescence.
Unlike in viral infection, the response to immunosuppression (i.e., glucocorticoids and for the long haul azathioprine) is generally good and the illness generally remits after a few years. (Anti-LMK-1 disease is less likely to respond and often does not remit and often relapses, requiring long-term maintenance). The common protocol, which often cures, is based on azathioprine (NEJM 333: 958 & 1004, 1995; update on why some patients tolerate it poorly: Dig. Dis. Sci. 51: 968, 2006).
We suggest following the course of the disease with biopsy, since liver enzymes correlate rather poorly with histologic progression.
* Future pathologists! Here's your scoring system (J. Hep. 31: 929, 1999)
- +2 if you're a female patient
About 85% of these people can achieve remission with today's treatments. Transplantation may eventually be necessary. After ten years, the transplant has about a 50/50 chance of being involved by recurrent disease (Gut 52: 893, 2003; update on the natural history of recurrent autoimmune hepatitis Dig. Dis. Sci. 57: 2248, 2012).
PRIMARY BILIARY CIRRHOSIS: An autoimmune disease caused (we don't know exactly how) by antibodies against pyruvate dehydrogenase ("anti-mitochondrial antibodies"). Lancet 362: 53, 2003. We'll talk more about this under "Liver Testing".
The bile ducts are selectively attacked by the immune system, eventually resulting in severe obstructive jaundice.
For some reason, the biliary epithelial cells express pyruvate dehydrogenase, or something very much like it, on their luminal surfaces (J. Clin. Invest. 91: 2653, 1993). This is evidently the target.
* The anti-nuclear antibodies often seen in primary biliary cirrhosis are usually directed at glycoprotein 210 and/or nucleoporin 62, on the nuclear surface pores.
* There are several known associations with HLA and Interleukin 12 genes: NEJM 360: 2544, 2009.
The histopathology begins with chronic inflammation (mostly portal, sometimes some interface hepatitis), and progresses through bile-duct obliteration and collateral formation to micronodular (why?) cirrhosis. For the details see Mayo Clin. Proc. 73: 179, 1998.
Less easy to explain are the frequent appearance of granulomas and Mallory's hyaline.
* Patients typically complain of severe fatigue, even early in the disease. One group attributes this to retained manganese (Gut 53: 587, 2004).
* Pitfall: Sarcoidosis can look exactly like PBC-with-granulomas, but the AMA is negative.
* Copper is likely to accumulate. Don't confuse it with Wilson's.
<24568> primary biliary cirrhosis, early; cirrhosis has not really developed yet, but portal areas are inflamed; you could not tell at this magnification that this is primary biliary cirrhosis
<24569> primary biliary cirrhosis, histology (i.e., the bile duct is gone)
Joel K. Greenson MD
Chronic inflammatory infiltrate
Primary biliary cirrhosis was found in the 1990's to be considerably more common than we had once thought, and to responds to therapy with bile salt analogues such as ursodeoxycholic acid (nobody knows why; Br. Med. J. 312: 1181, 1996) -- most cases get fairly good response; if more is needed, methotrexate and colchicine are helpful (Dig. Dis. Sci. 55: 3291, 2010).
* "Primary autoimmune cholangitis" looks something like primary biliary cirrhosis, but has high ANA titers and no anti-mitochondrial antibodies. See Am. J. Surg. Path. 18: 91, 1994; update on sorting out the autoimmune hepatitis family histologically Am. J. Clin. Path. 114: 705, 2000.
* IDIOPATHIC ADULTHOOD DUCTOPENIA is disappearance of the interlobular bile ducts; it may be asymptomatic (elevated GGT prompts its discovery) or progress to cirrhosis (NEJM 336: 835, 1997). More often, this is the result of drug-induced cholestasis that isn't recognized in time.
"Secondary biliary cirrhosis" is more likely to be just fibrosis, due to obstruction of the common bile duct, usually in chronic pancreatitis. If the stenosis is relieved, the fibrosis often regresses some (NEJM 344: 452, 2001).
DRUGS AND POISONS (a problem easily overlooked; reviews Gut 44: 731, 1999, NEJM 354: 731, 2006; including how to establish the relationship and warnings about what will happen if you leave the patient on the medication that's causing the liver disease)
As before, "all poisons are drugs, all drugs are poisons".
Drug-induced liver disease is a medicolegal nightmare. Since it is caused by hypersensitivity to medication, and since only a very few people are vulnerable to a particular drug, it's often missed in clinical trials.
To make the call, you want to see one of these:
- SGPT/ALT three times the upper limit of normal
Especially rough on the liver:
Any of these can produce massive hepatic necrosis. The toadstool and the acetaminophen overdose will produce massive hepatic necrosis; "Ecstasy" in recreational amounts is famous for the same (Transplant. Proc. 33: 2743, 2001). The others are more likely to produce a hepatitis-like picture.
ACETAMINOPHEN OVERDOSE is very common.
The drug is metabolized by two different pathways, one "safe", the other productive of noxious free radicals. Ordinarily, we use only the "safe" pathway, but when that is overloaded, the drug gets shunted into the bad pathway.
* We've already seen the "two-pathway" concept in our discussions of atherosclerosis and Alzheimer's disease. Stay tuned for the discovery of more "two-pathway diseases".
Three or four days after the overdose, the patient gets sick and lapses into hepatic failure. By this time, the drug itself may be mostly gone.
Future emergency room specialists: You can block the "bad" pathway using good old N-acetyl-cysteine, or "Mucomist", from the respiratory care department.
On biopsy or at autopsy, the necrosis is most obvious in the central areas. There's little or no inflammation.
* In England and Wales, acetaminophen is the popular method of suicide. Clever legislators required selling acetaminophen ("paracetamol") in smaller packages that required folks to unwrap each tablet. The suicide rate dropped dramatically (BMJ 346: f403, 2013).
BACTERIAL CHOLANGITIS ("ascending cholangitis", etc.) is suppuration involving bile ducts.
Joel K. Greenson MD
The underlying cause is almost always obstruction. Pretty much any gut bacterium can be the opportunist. E. coli is most common; clostridial gas gangrene of the liver is ultra-deadly.
As you would expect, patients are super-sick with the acute infection. Call a surgeon, since the bile has to be drained.
"Charcot's triad" is jaundice, right upper quadrant pain, and a bad fever.
The give-away on histologic exam is neutrophils within the bile ducts. Since there's obstruction, look for bile plugs, too.
LIVER ABSCESSES, in the U.S. are usually of bacterial origin, spreading either up the bile ducts ("cholangitis abscess" -- ascending cholangitis) or via the portal vein ("pyelophlebitic abscess" -- appendicitis, diverticulitis), or from septic emboli (bacterial endocarditis), or following a dirty wound.
Naturally, patients are super-sick, as with ascending cholangitis.
"Amebic abscesses", a misnomer, are areas of "anchovy paste" necrosis without much inflammation.
Effects of Garcinia cambogia (hydroxycitric acid) on visceral fat accumulation: A double-blind, randomized, placebo-controlled trial.
Hydatid cysts can become infected, forming real abscesses.
* PERICHOLANGITIS has been discarded as a term in pathology. Inflammation AROUND the bile ducts, typically extra lymphocytes, is very common at autopsy and no one knows what it means, if anything.
One could conjecture that the liver clears the blood of foul products of fatal disease, and that these are excreted in the bile and attract inflammatory cells.
Patients with ulcerative colitis and Crohn's generally have fibrosis around the bile ducts (SCLEROSING CHOLANGITIS) and often biliary obstruction / biliary cirrhosis.
Or one can have idiopathic PRIMARY SCLEROSING CHOLANGITIS, a curious, probably-immune-mediated entity. The extra-hepatic bile ducts in these diseases come to look like uneven strings of beads. Under the microscope, there is onionskin fibrosis around the intrahepatic bile ducts. Review Lancet 382: 1587, 2013.
* The majority of these patients have positive p-ANCA, often with curious specificities (Am. J. Med. 105: 393, 1998; Gut 44: 886, 1999.)
More recently, there are claims that there are distinctive autoantibodies against biliary epithelium (Gastroent. 132: 1504, 2007), and this seems to be holding up.
Medical therapy does not slow the progression of this disease. Many of these people need liver transplants, and the disease tends to recur in the transplanted organ.
* Sclerosis of the bile ducts is one feature of IgG4 sclerosing disease. More about this when we understand it.
* Perhaps 20% of folks go on to develop cholangiocarcinoma.
No inflammation, just no ducts
Onion-skinning around bile duct
Malaria can load the Kupffer cells with pigment, but seldom causes hepatic dysfunction.
KALA-AZAR (a vicious form of leishmaniasis ) packs Kupffer cells with organisms but does not interfere with liver function.
INFECTIOUS MONO from any of the usual causes can produce elevated transaminases and/or mild hepatocyte failure.
SECONDARY SYPHILIS can give an acute hepatitis, while TERTIARY and especially CONGENITAL syphilis are noted causes of hepar lobatum, due to scar contraction.
Don't forget LEPTOSPIRA in unexplained jaundice, especially if there is hemolysis.
* PENICILLIUM MARNEFFEI is an opportunist in AIDS, especially in Southeast Asia (Arch. Path. Lab. Med. 128: 191, 2004).
Increased pressure in the portal venous system, for whatever reason (usually increased resistance to flow and/or increased anastomoses with the arterial circulation).
Portal vein obstruction / compression
Thrombus (typically from tumor invasion, hypercoagulability, or polycythemia vera)
Tumors (hepatic, biliary, pancreatic)
Really bad pancreatitis
Cirrhosis (both fibrosis of the vasculature, especially hepatic veins, and AV-shunting contribute)
* Central hyaline sclerosis without cirrhosis
Really bad fatty change
Alcoholism / "alcoholic hepatitis", etc.
Schistosomiasis (eggs plug portal vein radicles, leading to the infamous "pipestem fibrosis")
* Congenital hepatic fibrosis (a thankfully-rare birth defect, with very few veins in the expanded portal areas; one known locus is a variant autosomal recessive polycystic kidney disease gene, and hepatic fibrosis is common in the fully-expressed condition as well: Medicine 85: 1, 2006)
Osler-Weber-Rendu telangiectasisa (abnormal vascular communications: NEJM 343: 931, 2000).
Really bad right-sided heart failure
Regardless of cause, portal hypertension is troublesome.
Patients get ASCITES, or large accumulations of fluid in the abdomen. This is troublesome. Mechanisms of formation include
(1) the obvious increase in hydrostatic pressure in the venules;
(2) the increase (most mechanisms) in hydrostatic pressure within the hepatic sinusoids themselves (the "increased hepatic lymph formation" of "Big Robbins"; this stuff is likely to be rich in protein, since the hepatic sinusoidal "endothelium" is discontinuous)
(3) diminished circulatory volume due to low serum albumin, with a tendency of the kidneys to retain sodium and water. (BEWARE! If you give these patients a diuretic, you can send them into shock, kidney failure, "hepatorenal syndrome", etc., etc.)
Caused by cirrhosis
Dilated submucosal veins
(Ignore the "hyaline perisplenitis")
PORTO-SYSTEMIC SHUNTING results when blood from the guts finds other routes back to the right side of the heart.
This results in ESOPHAGEAL VARICES (which can bleed profusely), SEVERE HEMORRHOIDS ("anorectal varices", which can bleed profusely), and the distinctive CAPUT MEDUSAE around the belly-button.
* This also probably is the cause of the usually-mild IMMUNOGLOBULIN A NEPHROPATHY typical of cirrhotics (i.e., asymptomatic hematuria). IgA from the gut ends up in the kidneys, rather than being cleared by the liver.
FIBROCONGESTIVE SPLENOMEGALY produces big, firm spleens that often produce clinically significant hypersplenism (i.e., they make the person anemic, neutropenic, and/or thrombocytopenic). This is bad.
You can treat portal hypertension effectively by doing a porto-caval shunt operation. If the underlying problem is cirrhosis, this will result in blood flowing directly from the bowel to the systemic circulation, making hepatic encephalopathy much, much worse ("portosystemic encephalopathy"). But most people prefer this to dying of bleeding varices.
Sclerosing agents save the lives of patients during acute bleeds. Today, banding ("band ligation") is doing the same (Br. J. Surg. 86: 437, 1999.)
For lasting control, the patient is likely to have the shunt placed inside the liver itself, by the radiologist who passes a catheter down the jugular vein ("transjugular intrahepatic portosystemic shunt" -- now revolutionized by the development of the covered shunt which allows longer shunt patency AJR 199: 746, 2012).
* Old-fashioned "prophylactic sclerotherapy" of esophageal varices actually increased the risk of dying. Perhaps it just made whatever vein didn't get sclerosed into a bigger varix. NEJM 324: 1779, 1991.
Of course, portal hypertension isn't the only problem that the cirrhotic has. See "When the liver fails", above.
ALCOHOLIC LIVER DISEASE (Lancet 345: 227, 1995; Mayo Clin. Proc. 76: 1021, 2001)
Double normal weight
Joel K. Greenson MD
Alcohol vs. NASH
Woe to those who demand strong drink as soon as they rise in the morning, and linger into the night while wine inflames them!
Sir, I have known more old drunkards than old doctors.
"The Wine God's Procession"
Everybody knows alcohol is bad for the liver, but there is perennial confusion about the various patterns of liver injury and their outcome.
ALCOHOLIC STEATOSIS ("alcoholic fatty liver")
We've already reviewed why fat accumulates in liver cells damaged by alcohol.
To review: The drunken hepatocytes make too much fatty acid, make it into excess triglyceride instead of burning it, then can't complex the triglyceride to apolipoproteins, and can't export the lipoproteins they do make.
Current thinking supports popular wisdom that alcohol itself does the damage (in fatty change and the more severe forms of "alcoholic liver disease"). Poor nutrition doesn't help, either (i.e., few people make daily trips to the salad bar while on benders.)
If you've ever drunk a case of beer over a great football weekend, I bet you've had fatty liver. Did you notice? Probably not. The "disease" is usually just a pathology finding, unless:
Fatty liver is, by itself, completely reversible once the drinker sobers up. The same applies to fatty liver from other causes i.e., after bariatric surgery (Gastroenterology 130: 1617, 2006), in obesity, in ill-controlled adult-onset diabetes, in problem pregnancy, in galactosemia, in methotrexate toxicity, in Wilson's disease, and as a complication of a few rare disorders of lipid metabolism.
NOTE: "Microvesicular steatosis" (smaller vacuoles, usually several per cell) is typical of Reye's syndrome, problem pregnancies, mitochondrial problems (Gastroent. 108: 193, 1995), and toxicity from outdated-tetracycline poisoning, or some of the HAART drugs. It's also reversible; really, "microvesicular" steatosis can occur in any fatty liver.
* In my opinion, the "microvesicular vs. macrovesicular" distinction is of no value. I have seen only one Reye's autopsy, and it was pure macrovesicular fat. I've autopsied many, many problem drinkers, and the pattern is often mixed, and sometimes microvesicular-only. I addressed this question to the pathology on-line group in 1996, and there was no disagreement from a few hundred experienced pathologists.
NOTE: "Fatty change" confined to the stellate cells ("Ito cells") is vitamin A overdose. "Stellate cell lipidosis" is often due to vitamin A overdose or Retin-A: Am. J. Clin. Path. 119: 254, 2003.
* Of course, if you continue drinking, you're at serious risk to get cirrhosis, even if "you only had fatty change" on a biopsy. Bad prognostic indicators include giant mitochondria and mixed microvesicular and macrovesicular fat. See Lancet 346: 987, 1995.
ALCOHOLIC HEPATITIS (NEJM 360: 2758, 2009)
Much more serious. Here, we have inflamed liver cells with widespread liver cell death and some stranger things than fat in the liver cells. The process is worst in the centrilobular regions.
Alcoholic hepatitis comes on suddenly, usually after years of problem drinking. However, it's clearly a different entity from both common "fatty liver" and the all-too-familiar cirrhosis. The patient -- who may not even have had a drink for a few weeks -- suddenly comes in with jaundice (bilirubin 5 mg/dL or more), elevated transaminases, and signs of portal hypertension and liver failure. Typically there's also an increase in blood neutrophils.
The cause of alcoholic hepatitis -- the sudden appearance of a new disease after years of drinking -- has been a minor mystery of medicine for centuries. Today's thinking focuses on alteration of the permeability of the large bowel, allowing endotoxin to flow into the portal circulation. It activates Kupffer cells and causes them to produce TNF-α.
The process can kill a patient directly. If an anesthetic is required, this may precipitate liver failure. Or some Hippocrates who doesn't want to biposy the liver because of the known tendency to bleed will feel it to be enlarged and assign an erroneous diagnosis of cirrhosis.
On biopsy, surviving liver cells often bear MALLORY'S ALCOHOLIC HYALINE (not pathognomonic, but suggestive). This is masses of altered prekeratin fibers plus stress proteins. Free Mallory's hyaline is chemotactic for neutrophils.
Also look for GIANT MITOCHONDRIA, (* Yokoo bodies, after one of the professors who trained your lecturer), PAS-negative blobs in the cytoplasm.
* Mitochondria (giant or no) in alcoholics' livers often have genetic damage, presumably because alcohol generates toxic free radicals inside them (Gastroent. 108: 193, 1995). This is one more putative mechanism of fatty liver. How?
The process tends to be worse in the central regions, but no area is spared. Cholestasis is usual because of compromise of bile canaliculi, with bile lakes and bile plugs. At the same time, the bile ducts may proliferate within the portal areas.
As the liver cells die off, look for FIBROSIS, notably around the central veins ("central hyaline sclerosis"; see Virch. Archiv. 614: 11, 1989; Postgrad. Med. J. 76: 280, 2000). This won't go away, and seems to be a rapid route to cirrhosis. (* You may be told that alcoholic hepatitis always precedes alcoholic cirrhosis; there's no reason to think this is true.)
<39929> alcoholic hepatitis, good Mallory's hyaline
<26702> alcoholic hepatitis, good Mallory's hyaline
<08832> alcoholic hepatitis with fibrosis; there is no good hyaline; cells are becoming entrapped in the fibrous tissue
<21056> "alcoholic hepatitis", looks like early cirrhosis to me
<26693> "alcoholic hepatitis", looks like early cirrhosis to me
The treatment is sobriety, and perhaps medications or lactobacilli to alter the gut flora; watch for TNF-blockers.
Again, the histology is not pathognomonic for alcoholism. The heart-drug amiodarone in particular is infamous for producing the same histopathology, and post-ileal bypass hepatitis, Wilson's disease (shouldn't miss this one!), NASH, and * East Indian childhood cirrhosis (copper toxicity in the genetically-predisposed; J. Path. 195: 264, 2001) can be dead-ringers.
If you are actually in the hospital and your primary diagnosis is alcoholic hepatitis, you probably have it very, very bad. explaining why the mortality figures in some studies are so high (for example, J. Clin. Gastro. 40: 833, 2006).
Fortunately, if you sober up, all that will remain is whatever minor scarring has occurred. The liver cells will regenerate nicely, and your liver will probably be fine.
ALCOHOLIC CIRRHOSIS ("Laennec's cirrhosis", other names)
Exactly what causes the progression (if it is a progression) from reversible changes (fatty change, Mallory bodies, inflammation) to irreversible (?) disease (i.e., fibrosis-cirrhosis) is obscure.
Easy to remember -- if you drink less than six beers per day / four glasses of wine per day, cirrhosis is unlikely. In order to get cirrhosis, one needs at least 15 pint-years (i.e, a pint of the hard stuff per day for fifteen years, three pints a day for five years, or similar). Many cirrhotics have much more. Yet 2/3 of heavy drinkers die without cirrhosis. Nobody knows why.
At first, the liver is big because of widespread hepatocyte overgrowth and fatty change from ongoing drinking. Later, with advanced scarring and enforced sobriety, the liver becomes rather small.
Microscopically, you'll see fibrosis and nodules instead of the normal architecture and proliferated bile ducts in the scar tissue (a good sign of alcoholism).
Early Laennec's cirrhosis has fine bands and a micronodular pattern. Late, the pattern becomes post-necrotic. When the scar tissue starts seriously obstructing bile flow, clinicians see jaundice and the pathologist sees bile plugs.
<20163> alcoholic cirrhosis, histology; trichrome stain
<10535> "alcoholic cirrhosis" closeup of a lobule; note the Mallory's hyaline and the neutrophils attacking it. There may be fibrosis elsewhere, but this merely looks like alcoholic hepatitis.
<39593> alcoholic cirrhosis; lots of bile duct proliferation (as is usual in alcoholic cirrhosis); edge of a nodule on each side of the screen
The cirrhotic must decide what he or she wants out of life. Continuing drinking is overall as lethal as untreated AIDS. Sobriety gives maybe a 90% chance of not dying of the cirrhosis within the next five years.
* During the early 1990's, liver transplants for alcoholic liver disease got discussed as showcasing problems with our "no-guilt" / "you have a right" ideas. "Unconstitutional discrimination and a violation of the Americans with Disabilities Act" or not (the story of Mr. Bush's 1992 policy change is now history), good used livers and other resources are (as always) in limited supply. See Gastroent. 102: 1806, 1992 (the now-famous Pittsburgh study), JAMA 265: 1295, 1991; JAMA 266: 213, 1991; Br. Med. J. 299: 693, 1989. Half of alcoholics who receive liver transplants return to problem drinking within one year (Gut 43: 140, 1998), but the good news is that they seldom wreck their new livers in doing so (Gut 45: 421, 1999). In the late 20th century, a few philosophers continued to maintain that alcoholics "may justifiably be given lower priority than others in receiving these [limited] resources" (J. Med. Philos. 23: 31, 1998). However, the most recent article I could find was in Transplant International 14: 170, 2001 (essentially, lifelong alcoholics are no more responsible for their ruined livers than are babies with biliary atresia). Uh, sure. The "ethical debate" seems to be over and alcoholics are competing on an equal basis for liver transplants with the dying babies. The third-party payers now require six months of abstinence from alcohol, which is unverifiable and unenforcable (J. Med. Ethics 32: 263, 2006) -- and a large percentage return to alcohol abuse when they get their new liver. Update from the ethicists NEJM 365: 1836, 2011. ("We only transplant alcoholics who are sobered up, have a strong support network, and no major psychopathology.") Of course, an alcoholic might get some slight sympathy if someone who ruined their liver doing intravenous drugs or sexual promiscuity or taking medicines with suicidal intent (Liver Trans 17: 1111, 2011) gets priority. Especially if we continue to make it difficult to obtain organs for transplantation, this will eventually start getting media attention -- the truth is that I'm surprised it hasn't already. Strangely, having been a marijuana smoker absolutely disqualifies people from receiving a liver transplant in most jurisdictions (Curr. Op. Org. Transpl. 15: 249, 2010) although there is evidence that this does not have any negative impact on people before or after transplant. Tobacco smokers may or may not be barred from receiving a liver; they do worse than non-smokers. Nowadays, anyone with enough money can go to China and come back with a new liver from an executed prisoner (Clin. Transp. 23: 831, 2009); a few "moral high ground" ethicists say it's immoral for US physicians to treat people who have done this (Am. J. Bioethics 10: 3, 2010) -- what do you think?
NON-ALCOHOLIC FATTY LIVER DISEASE -- non-alcoholic steatohepatitis, NASH, non-alcoholic fatty liver diseae, NAFLD (Am. Fam. Phys. 73: 1961, 2006; pathologists see Am. J. Clin. Path. 128: 837, 2007; J. Clin. Path. 60: 1384, 2007; Gastroent. 134: 1682, 2008; NEJM 363: 1341, 2010); BMJ 343: d3897, 2011; Gut 60: 1152, 2011 -- "what's new under the microscope"); JAMA 313: 2263, 2015.
NASH -- non-alcoholic steatohepatitis, fatty change into which acute inflammation, necrosis and fibrosis can creep -- is a poorly-understood but very real, very common condition that is only now getting the attention it deserves.
The JAMA article, cited above, claims that a majority of older obese and older diabetic folks have this and have fibrosis as a result; the pathology community is simply not seeing this at autopsy, but I don't doubt that NASH is at least a marker for bad health.
In countries where little alcohol is consumed and there is not much hepatitis or schistosomiasis , this is the most prevalent liver disease.
The anatomic pathology is much like alcoholic liver disease, with fatty change, often Mallory hyaline, and sometimes even cirrhosis (not so vicious as other forms of cirrhosis, but still sometimes requiring transplant -- Hepatology 43: 682, 2006).
* One tip-off that this is NASH is "chicken-wire" perisinusoidal fibrosis around hepatocytes in the central region. It is not pathognomonic, and to my eye is the hyalinization of the microvasculature already known to happen in the liver in diabetes.
There is always insulin resistance as well. Presently, discussions of pathophysiology emphasize the "adipokines" TNF-α and leptin, produced by bodyfat and causing insulin resistance. TNF-α is considered responsible for the cell injury, and leptin for fibrosis. The whole business is still very puzzling (Am. J. Path. 169: 846, 2006; Dig. Dis. Sci. 53: 1099, 2008); new players Gastroent. 134: 556, 2008; Am. J. Clin. Nutr. 89: 558, 2009.
The disease now easily the most common chronic liver disease in children and teens in the industrialized world, and many of these kids have fibrosis (Gastroent. 135: 1961, e2, 2008; Gastroent. 136: 160, 2009).
The mainstay of therapy has historically been weight loss and exercise in the overweight, masterful inactivity and perhaps metformin in the non-overweight (Med. Clin. N.A. 80: 1147, 1996; rationale for metformin Am. J. Gastro. 98: 2093, 2003). Exercise works for the mouse model (Diabetes 60: 2720, 2011). Betaine as a remedy: Am. J. Gastro. 96: 2534, 2001; Am. J. Gastro. +2 ), and not ferric (Fe +3 ) iron, is absorbed across the "mucosal barrier", mostly in the duodenum. It is complexed to a protein called NRAMP-2 (no diseases here yet) that transports much more efficiently when body iron stores are low. So the amount of iron absorbed varies inversely with the amount of ferritin already present in the duodenal epithelial cells, which in turn reflects total body iron stores. Iron absorption by the gut also increases when there is increased normoblastic activity. (The mechanism remains unknown; the latest stuff Blood 96: 4020, 2000.) Absorption is mildly increased in hemolytic anemias or after hemorrhage. Absorption is more markedly increased in "ineffective erythropoiesis", notably in severe sideroblastic anemia and thalassemias. Huge doses of dietary iron can override the regulatory mechanism.
Iron atoms are slowly released into the plasma, where they are bound to the globulin transferrin. The amount of transferrin present is also regulated, so that more will be present when more iron is required. The iron is then carried where it is needed. (* Transferrin will only carry ferric iron, while most of the other forms of iron are ferrous.) Likewise, when a red cell (or any other cell) is destroyed, its iron is carried away by transferrin. Extra iron is stored, mostly in the liver and bone marrow. In health, it is available for incorporation into RBC's or for transport by transferrin should a shortage develop.
Storage iron (somewhere in the range of 1 gm in most people) exists in two principal forms. (1) FERRITIN is a bit of iron at the center of a protein micelle. The protein shell explains the negative Prussian blue stain. This is the short-term storage form. It is the form found, for example, in bone marrow when it is soon to be incorporated into new RBC's. (2) HEMOSIDERIN is aggregates of ferritin with much of the protein gone. This is "Prussian blue positive" iron. It is a less labile storage form that accumulates when there is excess ferritin. (* "Hemosiderin" is an archaic name chosen by von Recklinghausen. "Exogenous hemosiderin" is an iron-protein complex that forms around sites of iron injection and foreign bodies composed of iron). Hemosiderin is the yellow pigment in the halo surrounding a bruise. Tip: If an injured area is pigmented yellow three months after bruising, the patient probably has iron overload.
Humans have no special mechanism for excreting excess absorbed iron. There is ordinarily a loss of 1 mg/day or so through GI and skin cell turnover and microhemorrhages into the gut and GU tracts. A typical menstrual period results in a loss of 10-20 mg of iron. During the course of a pregnancy, the fetus absorbs 500-1000 mg of iron from the mother's bloodstream. The fetus "gets priority" and often the mother becomes iron-deficient. Donating a 500 mL unit of blood removes approximately 250 mg of iron from the body.
Iron does harm to cells by generating free radicals.
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Primary iron storage problems are very common, under-diagnosed, easily and inexpensively detected, potentially fatal, and very treatable. And these patients are often considered hypochondriacs for many years before the diagnosis is finally made (Ann. Int. Med. 101: 707, 1984). During the early 1990's, it was finally appreciated that around 1 man in 200 is affected (NEJM 318: 1355, 1988). HEMOSIDEROSIS ("systemic siderosis", etc.): increased total body iron (as ferritin and hemosiderin), from any cause. Most of the excess iron is in the reticuloendothelial cells. Spill-over into parenchymal cells is what can cause trouble. It is now known that 13% of people carry an autosomal gene (HFE, within the HLA complex; update Arch. Int. Med. 166: 294, 2006) for excessive iron absorption via the gut and too-easy entry of iron into the liver cells. Homozygotes have worse problems; thankfully, we have finally come to recognize this as "the most common genetic disorder in populations of European ancestry": Am. J. Med. 119: 391, 2006; the vast majority of patients of Northern European stock have a C282Y mutation, and around 0.7 of people of Northern European ancestry are homozygous for the allele (update NEJM 358: 221, 2008; of these, one man in 4, and one woman in 10 is sick from it). H63D is common worldwide. Depending on diet and iron losses, these people may or may not express their PRIMARY HEMOSIDEROSIS.
HEMOCHROMATOSIS is hemosiderosis that has damaged parenchymal cells. Total body iron stores in excess of ten gm are very dangerous. In classic cases, total body iron stores often exceed 100 gm. PRIMARY HEMOCHROMATOSIS (formerly "idiopathic", now "familial", "genetic", "hereditary", or "HLA-linked"): in which the problem is greatly increased absorption of iron from the gut. These are "primary hemosiderosis" people in which the iron overload causes illness. Perhaps 1 man in 200 will be symptomatic with this during life, and thankfully we are diagnosing it more often. Review Am. Fam. Phys. 65: 853, 2002; Lancet 370: 1855, 2007. Update on screening (from the USPSTF): Ann. Int. Med. 145: 204, 2006. So do you screen using transferrin saturation (which is awfully sensitive and not very specific), the HFE gene (which is too expensive), or a serum ferritin (which picks up the people at risk for cirrhosis, albeit late, and is also up in acute or ongoing liver abuse/disease)? The case for ferritin: Blood 111: 3373, 2008. Expect continued disagreement.
* Other loci encode rare, severe forms. See below for an update.
SECONDARY HEMOCHROMATOSIS most often occurs in thalassemia major and in severe sideroblastic anemias. (Before it's symptomatic, of course, it's "secondary hemosiderosiss"). In these conditions, there is greatly increased iron absorption through the gut, and the patient requires many blood transfusions with no way of disposing of the iron load. Obviously you cannot treat these patients by bleeding (why not?) Deferoxamine is life-saving in thalassemia major: NEJM 331: 567, 1994.
So, in primary hemosiderosis and hemochromatosis, the problem is that iron is absorbed too easily through the gut. A patient homozygous for primary hemochromatosis who donates blood every eight weeks will remain iron-depleted. The tendency is encoded at HFE (Proc. Nat. Acad. Sci. 94: 2534, 1997 review, was HLA-H), discovered in 1996 in the HLA complex on chromosome 6, very closely linked to HLA-A and much like it; mouse hemochromatosis is caused by a bad beta2-microglobulin gene (Proc. Nat. Acad. Sci. 93: 1529, 1996) while the abnormal HLA-H doesn't bind properly to its microglobulin component. (* HLA-A3, B7, and B14 are often present, but the defect is linked with the chromosomes. Almost all B14 owners have the hemochromatosis gene, which is one reason (out of three) that your lecturer is confident that he carries it.) The frequency of the allele is about 14 out of every 100 chromosome 6's. Iron losses due to menstruation and pregnancies prevent expression primary hemochromatosis from ever developing in most women with the gene(s). Primary hemochromatosis is diagnosed nine times more frequently in men.
The classic hemochromatosis triad is liver trouble, diabetes mellitus, and skin discoloration. Today's list of major problems also includes cardiac rhythm disturbances, cardiac pump failure, and loss of sexuality. The liver may be enlarged on physical exam, or transaminases may be a bit high (South Med. J. 83: 1277, 1990). Around half of identified hemochromatosis patients develop overt diabetes mellitus. Since the 1990's, it has been considered good practice to screen everybody for iron overload (Gastroenterology 107: 453, 1994.) Most get the peculiar skin discoloration to some degree. The classic form of the disease is usually fully expressed around age 40-60 years. Patients, however, say their ill-health began during their 20's (Am. Fam. Physician 29: 55, March 1984).
LIVER DISEASE is the most serious problem in the majority of diagnosed hemochromatosis patients. The hepatocyte lysosomes and mitochondria are packed, and total liver iron stores are often more than one hundred times normal. There is often extensive fibrosis prior to the onset of symptoms (Arch. Int. Med. 166: 294, 2006), helping explain the classic observation that the liver enlarges even before cirrhosis develops. (The fibrosis reverses on iron removal unless cirrhosis is fully-developed.) The radiologist may notice it is unusually radio-dense. Micronodular cirrhosis (scarring that ruins the architecture of each lobule) is usually present by the time the diagnosis is made. When caused by hemochromatosis, this is called "pigment cirrhosis"). For the degree of fibrosis, the liver works surprisingly well, and clinical manifestations of cirrhosis are less severe than in alcoholic cirrhosis. However, cirrhosis is general considered irreversible and will finally kill the patient unless something else does first. (And something else usually does; only 25% of patients diagnosed to have primary hemochromatosis die of cirrhosis.) Once cirrhosis due to hemochromatosis has developed, the patient is at great risk for hepatocellular carcinoma (and to a lesser extent cholangiocarcinoma; histology Am. J. Clin. Path. 116: 738, 2001; hepatocellular carcinoma in iron overload without cirrhosis Am. J. Med. Sci. 334: 228, 2007). This is fatal and kills another 30% of patients diagnosed to have primary hemochromatosis.
Although more iron is deposited in the pancreatic acinar cells than in the ISLETS OF LANGERHANS, around 50% of patients have enough damage to their beta cells to develop symptomatic glucose intolerance.
CARDIAC INJURY is also caused by iron overload. Many hemochromatosis patients have pump failure and/or rhythm disturbances, either of which can be disabling or fatal. This is the other leading cause of death in iron-overloaded people. (How many of these deaths are assumed to be due to some other disease process? No one knows.)
ENDOCRINE INJURY is an additional problem. Patients are commonly troubled first by loss of libido, and eventually lose their secondary sex characteristics. Testicular atrophy secondary to pituitary failure with deposition in anterior lobe and Leydig cells too. It is quite reversible. Loss of testosterone in both men and women is now considered the explanation for the osteoporosis that develops in hemochromatosis patients (Ann. Int. Med. 110: 430, 1989). In addition, the adrenals, thyroid, and parathyroids are likely to be damaged, with various endocrine insufficiency syndromes. (* The role of "melanocyte stimulating hormone" in "bronze diabetes" is dubious.)
JOINT INJURY caused by iron overload (Arth. Rheum. 63: 286, 2011) is yet another major problem. Iron deposition in synovium results in synovial hyperplasia and erosion of bone and cartilage, eventually ruining the joint. In hemochromatosis, this usually affects the fingers, and is a problem for 50% of patients. In addition, the knees (and other weight-bearing joints) of hemochromatosis victims occasionally get accumulations of pyrophosphate crystals ("pseudogout", chondrocalcinosis).
SKIN PIGMENTATION in hemochromatosis is primarily due to increased melanin. (* Iron inhibits the enzyme that normally breaks down melanin.) Melanin imparts the "bronze" color; if there is enough hemosiderin in the skin, the combination looks "slate-gray".
Sepsis: For some unknown reason, Vibrio vulnificans (a raw seafood bug), Pasteurella pseudotuberculosis and Yersinia enterocolitica are much more pathogenic in the presence of iron overload. In 2011, the death of a CDC researcher from the relatively nonvirulent of plague with which he was working was attributed to his hemochromatosis (yes, they missed it even in a CDC worker -- NEJM 364: 2563, 2011). Even E. coli may get a boost in hemochromatosis (Am. J. Med. 87(3N): 40N, 1989).
You'll learn to make the diagnosis soon. In primary iron storage disease, it is important to make the diagnosis early. By the time the patient is obviously sick with hemochromatosis, he is 40 years old, has at least 20 grams of iron stored, has cirrhosis, and will probably be dead within ten years (though you can still help). If you find the tendency to accumulate iron, do this:
* "Why don't you give an iron chelator instead?" Retinal damage from deferoxamine is supposedly reversible. Some new iron chelator drugs are available now, but I'd still stick with the no-drug approach.
Secondary hemosiderosis and hemochromatosis: Nowadays, there is a tendency to transfuse sickle cell patients heavily in the hope of preventing stroke. Patients with severe thalassemia, Blackfan-Diamond, aplastic anemia and some of the myelodysplastic syndromes also become transfsion-dependent. The abnormal anatomy is similar to primary iron storage disorders, but more of the iron is usually in the Kupffer cells, not the hepatocytes until quite late. (People who overdo oral iron and make themselves sick tend to have a lot of hemosiderin in both hepatocytes and Kupffer cells.) Hemosiderosis due to red cell transfusions ("transfusional" or "iatrogenic siderosis") is unavoidable in patients with severe anemias of decreased production unless chelators are used (and these work well: Gastroent. 141: 1202, 1211). Remember, 100 red cell transfusions delivers 25 gm of iron! This is more than enough to produce hemochromatosis. These patients are now being treated with the new iron chelator drugs (update NEJM 364: 146, 2011) which are fairly well tolerated.
* Future pathologists: If you see lots of iron in both the Kupffer cells and the macrophages of the portal area, the patient has for whatever reason been taking a great deal of oral iron and is probably otherwise healthy, though they should stop the oral iron.
Hemosiderosis due to chronic alcohol abuse results from increased absorption of iron through the gut. The mechanisms are obscure, and this fact makes it hard to distinguish pigment cirrhosis from alcoholic cirrhosis. A few old-timers blame iron-rich wine for hemosiderosis in alcoholics. (A few wines are adulterated with iron, with up to 50 mg/mL. Most have much less). See Arch. Int. Med. 112: 184, 1963. Of course, if a hemochromatosis patient drinks heavily, the liver is doomed (Gastroent. 122: 281, 2002).
Vitamin-and-mineral faddists can occasionally make themselves chronically sick by iron-overloading themselves. (This is difficult to do and probably requires the genetic predisposition. See J. Roy. Soc. Med. 77: 690, 1984.) The Bantu people ingest 100 mg or more of iron daily from beer brewed in "iron pots" (really, discarded steel oil-drums). They tend to get hemosiderosis ("Bantu siderosis"), and a few get pigment cirrhosis. (Again, genes must be important; we now know that a Bantu beer-drinker with one dose of the hemochromatosis gene will probably get hemochromatosis; NEJM 326: 95, 1992.)
You'll screen for common hemochromatosis by checking the transferrin saturation levels, and confirm by serum ferritin levels. The current cutoffs ("transferrin saturation over 45% for women or 50% for men") probably miss too many people (Am. J. Med. 120: 999, e1-7, 2007). The actual iron assays on liver biopsy tissue will probably be replaced soon by MRI (Lancet 363: 341 & 357, 2004).
Hemosiderosis due to increased or ineffective erythropoiesis ("hematopoietic siderosis", typically when there is longstanding hemolysis), mild hemosiderosis is usual because of increased absorption of iron through the gut. In the severe thalassemias and sideroblastic anemias, red cell transfusions are required, erythropoiesis is ineffective, and absorption of iron through the gut is greatly increased. The iron overload progresses to fatal hemochromatosis. These are the patients who are most often treated experimentally with iron chelator drugs.
PORPHYRIA CUTANEA TARDA is a hereditary partial defect of uroporphyrin decarboxylase that is expressed best in the presence of iron overload. You'll encounter this if you keep your eyes open! Update Blood 95: 1565, 2000.
You'll diagnose hemochromatosis by labs, and confirm with genetic testing. Liver biopsy is still handy for judging the severity (Am. J. Clin. Path. 118: 73, 2002).
Here's a summary of the genes that are understood so far (Blood 106: 3710, 2005)
HFE: In the HLA class 1 locus. Hemochromatosis type 1. The protein is expressed throughout the body. To this day, we do not know exactly what it does; however, it's found complexed to transferrin receptor 1 in the duodenal crypts and it's reasonable to think it has to do with preventing overabsorption of iron through the duodenum. The healthy protein also apparently required in order to increase hepcidin levels when appropriate.
TFR2: Transferrin receptor 2. Hemochromatosis type 3. The protein is expressed by hepatocytes and interacts with transferrin. It's believed to sense the body's overall transferrin saturation. Mutation causes an uncommon illness identical to common HFE hemochromatosis but on the average more severe and earlier. It's also believed that a healthy TFR2 is required in order to increase hepcidin levels when required. Gastroent. 122: 1295, 2002.
HAMP: The gene for HEPCIDIN, expressed by liver and striated muscle. Hemochromatosis type 2B. The circulating hormone hepcidin controls absorption of iron through the duodenum and its release from macrophages. Deficiency is rare but causes a severe juvenile hemochromatosis. Hepcidin: Nat. Genet. 33: 21, 2003. Hepcidin rises in iron deficiency, falls in the iron-replete in health. It's inappropriately high in anemia of chronic disease (cytokine effects on the liver) and ineffective erythropoiesis (beta-thal major), promoting iron overload; exactly how it ties into common hemochromatosis is still being worked out.
HJV / HFE2: The gene for HEMOJUVELIN. This hormone binds to the protein NEOGENIN. Hemochromatosis type 2A. This seems to be the another hormone that inhibits absorption of iron through the duodenum. When normal, it's lowered by anemia, hypoxia, and iron deficiency, permitting a higher rate of iron absorption. Nat. Genet. 36: 77, 2004; mouse J. Clin. Inv. 115: 2187, 2005; hemojuvelin senses the amount of iron in the diet overall J. Clin Inv. 115 2180, 2005.
SLC40A1 (was SLC11A3): The gene for FERROPORTIN, which is the hepcidin receptor. Hemochromatosis type 4. Another protein expressed throughout the body. It seems to permit the exit of iron from cells -- its inhibition by hepcidin from angry macrophages and IL6-stimulated liver is the basis for anemia of chronic disease. Mutions here produce a dominant hemochromatosis with iron-overloading of body macrophages but not parenchymal cells, and normal or low transferrin saturation, and usually not the classic findings of hemochromatosis unless there is another gene. They do not give up their iron on phlebotomy, but develop "anemia of chronic disease". Autosomal dominant hemochromatosis ("ferroportin disease") is in fact most often due to deficiency in ferroportin (J. Clin. Inf. 108: 512 & 619, 2001; Blood 100: 692, 2002; Blood 106: 1092, 2005' update Gastroenterology 140: 1199, 2011).
CERULOPLASMIN: Aceruloplasminemia Gut 47: 858, 2000 (hepatocytes and Kupffer cells involved uniformly, no fibrosis, neurologic disease rather than liver failure; this is NOT Wilson's).
WILSON'S DISEASE ("hepatolenticular degeneration"; Mayo Clin. Proc. 78: 1126, 2003; Gastroent. 125: 1868, 2003; Lancet 369: 379, 2007)
Rare but very, very important. Don't miss this diagnosis. Untreated, it is lethal. Treated, it's harmless. You'll never diagnose it unless you think of it. And it ALWAYS masquerades as something else.
Wilson's disease is an autosomal-recessive problem in which the liver is unable to dispose of excess dietary copper via the bile.
The gene was cloned in 1997, and named ATP7B; it is (no surprise) a copper-transporting ATP-ase (Am. J. Hum. Genet. 61: 317, 1997).
* ATP7A is Menke's, an especially cruel X-linked neurodegenerative disease noted for producing "kinky hair."
Serum levels of ceruloplasmin, the copper transport protein, are often (but not always) low in Wilson's. This is probably because ceruloplasmin is ordinarily sent out of the liver cells bound to copper, and if it's unbound, it is degraded too rapidly.
More helpful for your workup, serum copper, not properly carried, spills copiously into the urine in Wilson's disease. This represents the only route of copper excretion, and it is inadequate.
Serum free copper (actually measured, not calculated) is an up-and-coming lab that seems sensitive and specific for Wilson's in the right setting (Am. J. Clin. Path. 131: 160, 2009).
Eventually, the copper accumulates, damaging liver, joints, brain (especially basal ganglia), proximal renal tubule (causing wasting of solutes) and red cells (mild ongoing hemolysis is the rule), and making the distinctive Keyser-Fleischer corneal ring (you probably won't see them without a slit lamp).
The copper itself probably damages the cells in which it accumulates, maybe by free radicals or inhibiting enzymes. * Future pathologists: Stain for copper using rhodaNine or rubeanic acid!
The histology in the liver passes through fatty change to a histopathology basically identical to alcoholic hepatitis to chronic hepatitis to micronodular cirrhosis to post-necrotic cirrhosis. At autopsy, you see an unforgettable bluish-coppery colored liver, and the same discoloration in the basal ganglia.
The treatment, of course, is to remove the copper with a metal chelator. Penicillamine works wonders, but it won't cure cirrhosis or restore dead neurons.
Lab diagnosis is treacherous. Serum ceruloplasmin is low more often than not, but this is a notoriously poor screening test. Staining the liver itself for copper is treacherous. Even assaying liver tissue for copper ("normal is less than 55 micrograms/gm of liver; Wilson's has more than 250") is unreliable because you may have sampled a regenerative nodule that's copper-poor, and copper is deposited near the portal areas whenever there is chronic cholestasis. I recommend a urinary copper assay.
Missing the diagnosis of Wilson's disease clinically is still a common blunder, especially when it presents as "mental illness" (update Gut 56: 115, 2007). The physician's mistake WILL cost the patient his/her long-term health or even life.
Joel K. Greenson MD
HEPATIC AMYLOIDOSIS: We cover this in "immuno". Amyloid accumulates in the vessels and space of Disse, and can eventually give a large, very firm liver that usually still functions acceptably. Past concerns about biopsying the liver in suspected amyloidosis seem to be groundless (Medicine 82: 291, 2003).
Joel K. Greenson MD
A host of drugs-poisons produce typical reactions in the liver. These range from predictable ("Take enough 'Tylenol' at once and your liver cells all die") to highly idiosyncratic ("Take 'Halothane' anesthesia a second time and there's a tiny chance that sensitivity will kill you.") "Inflammation" may mimic acute or chronic hepatitis.
Acetaminophen ("Tylenol"). Massive hepatic necrosis
Allopurinol. Granulomas (* infamous for looking like the ring granulomas of Q-fever)
Alpha-methyldopa. Inflammation, granulomas, massive necrosis (idiosyncratic)
Amiodarone. Inflammation, "alcoholic hepatitis" mimic, cirrhosis (idiosyncratic); kupffer cells loaded with phospholipid ("phospholipidosis")
Anabolic steroids. Cholestasis (at least)
Azathioprine. Fatty change, necrosis and regeneration in the central zones (Arch. Path. Lab. Med. 136: 618, 2012)
Chlorpromazine. Cholestasis (idiosyncratic)
Estrogens. Cholestasis (idiosyncratic), thrombosis (idiosyncratic)
Ethanol. Fatty change, alcoholic hepatitis, cirrhosis
Fenfluramine. Massive necrosis (idiosyncratic; a dozen Japanese find out what was really in their Red Chinese holistic-wholesome weight-loss pills beside lotus leaves and chrysanthemum petals: Ann. Int. Med. 139: 488, 2003)
Halothane. Massive hepatic necrosis (idiosyncratic)
<24392> "Halothane hepatitis" case; simply massive necrosis
* Hydrazine (a quack cancer remedy). liver necrosis (Ann. Int. Med. 133: 877, 2000).
Isoniazid. Looks like viral hepatitis (idiosyncratic) (especially >age 35)
*7nbsp;Lapitinib. for HER+ breast cancer; people with a certain HLA get liver toxicity.
Methotrexate. Necro-inflammation, cirrhosis (sometimes even at "safe" doses)
Oxyphenisatin (laxative). Inflammation ("lupoid hepatitis") (who'd abuse THAT?)
* Paraquat: Hepatocellular injury that resolves (early); necrosis of the bile duct cells (late)
Pennyroyal ("holistic herbal tonic" / amateur abortifacient) . simulates viral hepatitis (update on poisoning from Mayo's: Acad. Emerg. Med. 10: 1024, 2003)
* Phenylbutazone. Granulomas (who still uses THAT?)
* Rituximab. Cholestatic hepatitis
* Sulfa drugs. Granulomas
Tetracycline (outdated). Microvesicular fatty change (get rid of yours!)
* Total parenteral nutrition. Fatty change (nobody knows why; this and malnutrition are the major illnesses in which fatty change is likely to be periportal rather than central; Gastroent. 104: 286, 1993)
Valproic acid: Mixed hepatitis-like and cholestatic, or just fatty change
* Venlafaxine (antidepressant): Cholestatic hepatitis (Am. J. Surg. Path. 36: 1724, 2012).
* Future physicians: Whether or not a drug is dangerous to the liver is decided nowaday's by HY'S LAW. Hy Zimmerman's criteria: (1) AST / ALT go up to at least 3x the upper limit of the reference range; (2) and when the AST / ALT go up, at least some folks also have bilirubin go up to 2x the upper limit of the reference range without also raising alk phos (which would indicate it is only cholestasis; (3) and there's no other reason (viral hepatitis, medication). If Gilbert's is present, it can make it harder to interpret Hy's Law (Clin. Pharm. 91: 647, 2012).
REYE'S SYNDROME (Am. Fam. Phys. 50(7): 1491, 1994; NEJM 340: 1423, 1999; NEJM 340: 1377, 1999)
This poorly-understood, dread entity is an acute illness that follows another viral illness, usually 'flu or chicken pox, usually in a child or young teen.
The biphasic clinical story is typical.