Drug-Induced Liver Injury and Acute Liver Failure: Drug Injury and Liver Failure: Causes and Patterns

0:00Welcome to Board Pearls. This is episode one of two of the Drug-Induced Liver Injury and Acute Liver Failure chapter, in the Liver Disease module. This episode is drug-induced liver injury, from suspicion to mechanism to biopsy to the prototype poisoning. A woman on nitrofurantoin shows the three kinds of drug injury, who's at risk, how Hy's law and causality scoring guide the next step, and why an autoimmune-looking injury doesn't need lifelong treatment. A young bodybuilder shows why supplements belong in every history, and a man starting an antiretroviral shows the one genetic test that's required. A drinker on isoniazid shows why injury happens when one metabolic step outruns the next, and the patients after him show how valproate, methotrexate, statins, and amiodarone each follow their own rules. A man jaundiced a month after amoxicillin-clavulanate shows the recurring biopsy patterns and the drugs behind each. And a fasting drinker taking ordinary doses of acetaminophen shows the toxic thresholds, when the nomogram applies, and how N-acetylcysteine is dosed.

1:06Here's the first patient. A fifty-eight-year-old woman has taken nitrofurantoin nightly for eight months to prevent urinary infections. Now she has fatigue and jaundice. Her alanine aminotransferase, ALT, is six hundred twenty, her alkaline phosphatase one hundred forty, and her bilirubin four point one, with a normal international normalized ratio, INR. Her antinuclear antibody, ANA, is positive at one to three hundred twenty, and her immunoglobulin G, IgG, is high. Her viral tests are negative, and her ultrasound shows no biliary dilation. She takes nothing else, she says, apart from a calcium supplement.

1:49Acute hepatocellular injury with jaundice, negative viral tests, a clear ultrasound, and months of nitrofurantoin suggests drug-induced liver injury, here with autoimmune features. Essentially any drug, herbal product, or supplement can produce essentially any pattern of liver injury, so drug injury belongs in the differential of every new abnormality in the liver tests. The history covers prescriptions, over-the-counter drugs, herbals, supplements, and recent changes, each asked about by name, which is how her calcium supplement came up. Calcium isn't a known liver toxin, but the question had to be asked.

2:24Drug injury comes in three kinds. Intrinsic, or direct, hepatotoxicity is dose-dependent and predictable, appearing within days of a large enough exposure, and acetaminophen is the prototype. Idiosyncratic hepatotoxicity is dose-independent and unpredictable. It depends on genetic variation in drug metabolism and on immune recognition of self proteins the drug has modified, and it can appear days to years after the drug is started, typically at one to three months, with a peak at six to eight weeks. Indirect hepatotoxicity comes from the drug's effect on the immune system or on an existing infection, as with the checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab, and with hepatitis B reactivation after rituximab or chemotherapy, and its onset is over months. Hers is idiosyncratic, emerging months into a stable dose.

3:16Her sex and her drug put her in a recognized risk group. A prospective French study found about fourteen cases per one hundred thousand medication users, more than ten times what voluntary reporting captures. Drug injury is the most common reason a new drug fails late in development or is withdrawn, and in the United States Acute Liver Failure Study Group registry, drugs, acetaminophen included, account for nearly sixty percent of acute liver failure. Children carry unique risks, Reye syndrome from aspirin and fulminant injury from valproate, and adults over sixty carry more risk of isoniazid injury and of cholestasis. Women are overrepresented in the autoimmune-like pattern from minocycline, methyldopa, nitrofurantoin, and diclofenac.

4:02Other factors raise risk through specific mechanisms. Polypharmacy raises it through competition for the cytochrome pathways, chronic alcohol and malnutrition through glutathione depletion, obesity with fatty liver through drugs that disrupt fatty acid oxidation, and a prior drug injury from any drug. Chronic liver disease and cirrhosis don't raise the risk from most drugs, because a diseased liver makes less toxic metabolite, but injury in cirrhosis is more dangerous and can cause decompensation.

4:32Her jaundice makes severity the first concern, and it's judged by Hy's law. Drug injury with an ALT or aspartate aminotransferase, AST, over three times normal plus a bilirubin over two times normal, without obstruction, meaning an alkaline phosphatase under two times normal, and with no other clear cause, carries about a ten percent mortality. Injury severe enough to disrupt bilirubin excretion means enough functional liver has been lost that stopping the drug may not guarantee recovery, so the drug stops, the patient is admitted, and a transplant center is alerted. Progression to acute liver failure with encephalopathy raises mortality without transplant to about eighty percent.

5:12She meets Hy's law. Her ALT is far above three times normal, her bilirubin above two times normal, her alkaline phosphatase under two times normal, her ultrasound clear, and her viral tests negative. She's admitted, nitrofurantoin is stopped, and the transplant center is informed.

5:32Her pattern, by the R ratio, predicts her course. R is the ALT over its upper limit divided by the alkaline phosphatase over its upper limit, with a value over five hepatocellular, under two cholestatic, and two to five mixed. Hers is about sixteen, hepatocellular. Hepatocellular injury is more likely to progress to acute liver failure, while cholestatic and mixed injury are more likely to become chronic. In the United States registry, about half of cases were hepatocellular, a quarter cholestatic, and a quarter mixed. About seventeen and a half percent became chronic, lasting beyond six months, around seventy percent were jaundiced, and ten percent died or needed a transplant, with worse outcomes in patients with prior liver disease.

6:18Blaming nitrofurantoin needs a causality assessment. RUCAM, the Roussel Uclaf Causality Assessment Method, scores the timing of onset and recovery, the course after the drug is stopped, risk factors such as age over fifty-five and alcohol, competing drugs, exclusion of other causes, prior reports, and any rechallenge. A score over eight is highly probable, six to eight probable, three to five possible, one to two unlikely, and zero or less excluded. The parts matter more than the number. Her timing fits, other causes are excluded, and nitrofurantoin is a known offender, and the dechallenge, whether her tests improve off the drug, is part of the diagnosis.

7:01Her positive ANA and high IgG are explained by the drug, not by a second disease. About nine percent of registry drug injury is indistinguishable, on histology and serology, from idiopathic autoimmune hepatitis, with a positive ANA or smooth muscle antibody, a high IgG, plasma cell-rich interface hepatitis, and a response to steroids. The main offenders are nitrofurantoin, minocycline, hydralazine, and methyldopa, plus diclofenac and statins. Female sex, exposure for more than three months, and the human leukocyte antigen types HLA-DR3 or DR4 are the markers, which explains her long latency.

7:41The difference is what happens after the drug is gone. Drug-induced autoimmune-like hepatitis usually remits once the drug is withdrawn and doesn't need long-term immunosuppression, whereas idiopathic disease flares when steroids are tapered. Steroids in drug injury are reserved for this pattern and for checkpoint inhibitor hepatitis. A biopsy is reasonable when the tests don't improve after the drug is stopped, or when the patient is jaundiced.

8:05Her bilirubin keeps rising for a week after nitrofurantoin is stopped, so she has a biopsy, which shows interface hepatitis with plasma cells, and she starts prednisone. Her tests normalize over two months, and she tapers off without a flare, which confirms drug-induced autoimmune-like hepatitis. She's told never to take nitrofurantoin again.

8:26The second patient shows why supplements get asked about by name. A twenty-six-year-old man taking an anabolic steroid for bodybuilding has deep jaundice, a bilirubin of eighteen, and only a mildly raised ALT. Herbal and dietary supplements are the fastest-growing category of drug injury in the United States, about sixteen percent of registry cases, second only to amoxicillin-clavulanate among single agents. Anabolic steroids produce a striking cholestasis with a very high bilirubin and a mild ALT that can persist for months, but no bodybuilder in the registry died or needed a transplant.

9:02Other supplements are more dangerous than his. Green tea extract causes hepatocellular injury, kava causes hepatocellular and sometimes fulminant injury, and multi-ingredient weight-loss or energy products cause idiosyncratic injury in which the culprit often can't be identified. Herbal injury outside bodybuilding led to transplant in thirteen percent of registry cases, several times the rate for prescription drugs.

9:25Genetics matter mostly through HLA types, and the third patient shows the one that's actionable. HLA-B star fifty-seven oh one sharply raises the risk of abacavir hypersensitivity hepatitis and also of flucloxacillin cholestasis. DRB1 star fifteen oh one goes with amoxicillin-clavulanate cholestasis, and B star thirty-five oh two with minocycline injury. Only testing for HLA-B star fifty-seven oh one before abacavir is clinically actionable, and it's mandated, and abacavir is the drug to suspect when hypersensitivity hepatitis with rash and eosinophilia follows the start of an antiretroviral. A thirty-four-year-old man with human immunodeficiency virus, HIV, infection tests negative, so he starts it.

10:11Why a drug injures one person and not another comes down to metabolism, and the fourth patient shows it. A fifty-four-year-old man started isoniazid for latent tuberculosis seven weeks ago. He drinks four beers a night. His baseline liver tests were normal. Now he has nausea and fatigue, an ALT of four hundred ten, and a bilirubin of two point six. He asks whether he can push through.

10:35He has isoniazid hepatitis that meets Hy's law, and his drinking explains why he was at risk, through the mechanism behind most drug injury, reactive metabolites. Phase one reactions, dominated by the cytochrome P450 enzymes in the smooth endoplasmic reticulum, oxidize the parent drug into an intermediate that's often more reactive. Phase two reactions conjugate it with glutathione, glucuronate, sulfate, or glycine for excretion. Injury happens when phase one outpaces phase two. The intermediate then either binds hepatocyte proteins directly, a toxic injury, or modifies host proteins into antigens the immune system attacks, an immunoallergic injury, and the same drug can do either depending on cytochrome induction, glutathione stores, and HLA type.

11:26The cofactors act on those two steps. Inducers such as chronic alcohol, phenytoin, phenobarbital, and rifampin speed phase one. Alcohol, fasting, and malnutrition deplete glutathione. And inhibitors such as erythromycin, ketoconazole, fluconazole, and cimetidine slow the clearance of the parent drug.

11:48Acetaminophen is the textbook example. At therapeutic doses, more than ninety percent is glucuronidated and sulfated harmlessly, and about five to ten percent is oxidized, mainly by CYP2E1 and less by CYP3A4 and CYP1A2, into N-acetyl-p-benzoquinone imine, NAPQI, which glutathione neutralizes. The toxic dose is the point where NAPQI production exceeds the glutathione pool. So glutathione depletion, from chronic alcohol, fasting, malnutrition, an eating disorder, or HIV, and CYP2E1 induction, from chronic alcohol, isoniazid, rifampin, phenytoin, or phenobarbital, both lower the threshold.

12:39Isoniazid follows the same rule. NAT2 acetylates it to acetylhydrazine, which CYP2E1 oxidizes to a hepatotoxic intermediate, so slow acetylators, rifampin, and chronic alcohol all raise the risk. Four to twenty percent of patients develop raised aminotransferases and most adapt, but up to two percent develop clinically significant hepatitis with jaundice, amplified by age over fifty, female sex, alcohol, and rifampin. The risk rises steeply with age, to about twenty-one per thousand over fifty. Most isoniazid liver failure occurs in the first three months, which is why monitoring is monthly and concentrated early.

13:20He's over fifty, drinks daily, is seven weeks in, has an ALT over ten times normal, and is jaundiced, so he meets Hy's law and can't push through. Isoniazid stops, and he's counseled to stop drinking and to avoid acetaminophen, which both his drinking and the isoniazid make more toxic. His ALT normalizes over six weeks, and his latent tuberculosis needs a different plan.

13:44Other drugs injure by other mechanisms, and each sets its own monitoring. An eighteen-month-old girl on valproate for seizures develops vomiting, lethargy, and a high ammonia with only a modest rise in her aminotransferases. She has valproate hepatotoxicity, which poisons mitochondria. Valproate metabolites inhibit fatty acid beta-oxidation and deplete carnitine, causing microvesicular steatosis and hyperammonemia, and rarely fulminant failure with metabolic acidosis. A modest ALT doesn't mean mild injury when the mechanism is mitochondrial. Children under two with mitochondrial enzyme disorders, such as POLG mutations, are the highest-risk and textbook fatal cases. Her valproate stops, and carnitine is a standard adjunct that can reverse the hyperammonemia in mild cases. Chapter twenty-two covers the inherited mitochondrial disorders.

14:35With methotrexate, the ALT misleads in the other direction. A sixty-year-old woman with psoriatic arthritis, obesity, and diabetes has taken methotrexate for six years with a normal ALT. Methotrexate injures cumulatively, through folate antagonism and direct hepatocyte injury, producing steatosis and fibrosis, sometimes cirrhosis, with little inflammation, so a rising ALT is an unreliable early signal. Obesity, diabetes, alcohol, and pre-existing fatty liver compound the fibrosis, and she has two of them. So her monitoring is periodic liver tests plus a noninvasive fibrosis assessment such as FibroScan, not reassurance from her normal ALT.

15:18Statins are far safer than their reputation. They raise the ALT in roughly one to three percent of patients, almost always to less than three to five times normal, and adaptation is the rule. Severe injury occurs in about one in fifty thousand, and liver failure is exceedingly rare. They're safe to start with stable raised aminotransferases from fatty liver disease, and they rarely need stopping unless the ALT exceeds five times normal or the patient becomes jaundiced. Chapter twenty-one covers fatty liver disease.

15:51Amiodarone mimics a disease the patient doesn't have. It's amphiphilic, so it accumulates in lysosomal membranes and inhibits phospholipases, leaving lamellar lysosomal inclusions on electron microscopy, a pattern called phospholipidosis that it shares with chlorpromazine and chloroquine. On histology it mimics alcoholic liver disease, with steatohepatitis, Mallory-Denk bodies, and pericellular fibrosis in a patient who doesn't drink. The cumulative dose matters, and stopping it may not reverse the injury, because its tissue half-life is very long.

16:21The biopsy has its own logic, and the fifth patient shows how it's read. A sixty-seven-year-old man took amoxicillin-clavulanate for ten days for sinusitis and felt fine. Four weeks after finishing it, he developed itching and jaundice, with an alkaline phosphatase of five hundred twenty, an ALT of one hundred ten, and a bilirubin of seven. His R ratio is under two, his ultrasound shows no ductal dilation, and his anti-mitochondrial antibody, AMA, is negative. He doubts the antibiotic matters, since he stopped it a month ago.

16:55He has cholestatic drug injury from amoxicillin-clavulanate, and the delay is typical. A biopsy, if he needs one, would show one of a handful of recurring patterns, set by where the drug is activated, whether it's processed through the bile ducts or the hepatocytes, and the immune response it provokes. Centrilobular necrosis tracks the density of cytochrome P450, CYP, in zone three around the central vein. Cholestasis tracks drugs metabolized into bile or that interfere with the canalicular transporters, the bile salt export pump, BSEP, and MRP2. Granulomas track delayed-type hypersensitivity. Microvesicular steatosis tracks poisoning of mitochondrial beta-oxidation. And vascular injury tracks endothelial damage by alkaloids, or thrombosis and ectasia driven by hormones. Almost any drug can produce almost any pattern, so the biopsy narrows the list, and the answer comes from the pattern, the drug history, and the timing together.

17:58His pattern is pure cholestasis, bland canalicular cholestasis with bile plugs and minimal inflammation. Amoxicillin-clavulanate, the most common single agent in the United States registry, produces it two to six weeks after the course ends, which is why it's missed: the patient is well, the infection is gone, and nobody connects the two. Other cholestatic offenders are erythromycin and the other macrolides, anabolic and contraceptive steroids, which cause an especially bland cholestasis, oral contraceptives, chlorpromazine, and the azoles ketoconazole, fluconazole, and itraconazole.

18:33His injury could have gone further. Persistent cholestatic injury can progress to vanishing bile duct syndrome, a progressive loss of bile ducts, most often reported with amoxicillin-clavulanate, fluoroquinolones, azithromycin, sulfamethoxazole, carbamazepine, lamotrigine, allopurinol, and ibuprofen. It mimics primary biliary cholangitis and is told apart by the drug exposure and a negative AMA. His cholestasis lasts four months, a biopsy at three months shows bland cholestasis with preserved ducts, and his tests slowly normalize. He's told never to take amoxicillin-clavulanate again.

19:13Had his R been over five, his biopsy would have shown a hepatocellular pattern, the most common and the most likely to progress to acute liver failure. Zone three necrosis is the textbook acetaminophen lesion, where CYP2E1 is densest, and it's also seen with isoniazid, methyldopa, halothane, and historically carbon tetrachloride. Diffuse hepatocellular injury that mimics viral hepatitis, with portal lymphocytes, lobular inflammation, and apoptotic Councilman bodies, comes from isoniazid, nitrofurantoin, allopurinol, diclofenac, and statins, which is why the viral panel comes first. Massive necrosis with confluent lobular collapse is the fulminant picture, from any drug.

19:56Mixed injury, with an R between two and five, shows portal inflammation and bile duct injury, classically from trimethoprim-sulfamethoxazole, phenytoin, and azathioprine. A thirty-nine-year-old woman started on phenytoin five weeks ago now has a rash, fever, swollen lymph nodes, eosinophilia, and mixed injury. She has drug rash with eosinophilia and systemic symptoms, DRESS, which typically appears two to eight weeks after the drug is started, so a rash weeks into treatment points to a drug started over a month ago. Her phenytoin stops, and another anticonvulsant replaces it.

20:30Granulomatous hepatitis, with non-caseating epithelioid granulomas, comes from allopurinol, sulfonamides, hydralazine, quinidine, phenytoin, and isoniazid. It overlaps with sarcoidosis and is told apart by its timing and its resolution off the drug, but sarcoidosis, tuberculosis, brucellosis, Q fever, primary biliary cholangitis, and lymphoma are excluded first.

20:57Steatosis comes in two forms that mean different things. Macrovesicular steatosis, large droplets that push the nucleus aside, comes from glucocorticoids, methotrexate, diltiazem, and tamoxifen, and amiodarone produces its alcohol-like steatohepatitis. Microvesicular steatosis, many small droplets that don't displace the nucleus, signals mitochondrial toxicity from tetracycline, valproic acid, the older antiretrovirals zidovudine, didanosine, and stavudine, and salicylates in Reye syndrome. It's the more dangerous pattern, with hyperammonemia and metabolic acidosis despite modest aminotransferases, so a patient with HIV on stavudine with lactic acidosis, an enlarged liver, and a mild ALT rise has serious injury. Phospholipidosis comes from amiodarone, perhexiline, sulfonamides, tamoxifen, and griseofulvin.

21:51Vascular injury is suspected when portal hypertension or Budd-Chiari syndrome appears without much hepatocellular injury. A sixty-one-year-old woman who has drunk a daily comfrey bush tea for months has rapid weight gain, painful hepatomegaly, jaundice, and ascites. She has sinusoidal obstruction syndrome, formerly veno-occlusive disease, from the pyrrolizidine alkaloids in comfrey, Senecio, and Crotalaria teas, the other main cause being myeloablative chemotherapy before stem cell transplant. The biopsy shows sinusoidal occlusion and centrilobular congestion. She stops the tea, which she hadn't thought of as a drug.

22:30Other drugs cause vascular injury too. Oral contraceptives cause peliosis hepatis, which is blood-filled cystic spaces, Budd-Chiari syndrome from hepatic vein thrombosis, and hepatic adenomas, and anabolic steroids share the peliosis association. Azathioprine and six-thioguanine cause nodular regenerative hyperplasia, small regenerative nodules without bridging fibrosis that produce non-cirrhotic portal hypertension, and didanosine and stavudine do the same. Chapter twenty-three covers non-cirrhotic portal hypertension.

23:02The prototype intrinsic injury comes last, and the sixth patient shows how it can happen at ordinary doses. A forty-four-year-old man who drinks heavily caught the flu five days ago, stopped drinking, and barely ate. He took about four grams of acetaminophen a day for fever and aches, never more than the bottle allowed. Now he's confused and vomiting. His ALT is eight thousand two hundred, his AST nine thousand, his bilirubin two point one, and his INR three point four. His acetaminophen level is low. His family insists he couldn't have overdosed.

23:38Aminotransferases over five thousand with coagulopathy and confusion, in a fasting drinker taking acetaminophen, is acetaminophen hepatotoxicity with acute liver failure, even at doses within the label. Acetaminophen is the prototype intrinsic hepatotoxin and the leading cause of acute liver failure in the United States and the United Kingdom. Once glutathione is exhausted, NAPQI binds hepatocyte proteins, especially mitochondrial proteins, and zone three dies first. His drinking induced CYP2E1, his fasting and drinking depleted glutathione, and stopping alcohol a few days earlier didn't undo the induction, so an ordinary dose overwhelmed him.

24:18The toxic thresholds differ between a single overdose and chronic use. A single acute ingestion of seven and a half grams or more in an adult, or over one hundred fifty milligrams per kilogram in a child, enters the toxic window, and suicidal overdoses typically exceed ten to fifteen grams. Chronic supratherapeutic ingestion, called therapeutic misadventure, is more treacherous. In a drinker, a malnourished patient, or a fasting patient, four grams a day or less for several days can be fulminant, and these patients present late.

24:50His presentation is the typical one. The usual patient is a chronic drinker with a viral illness who stops drinking and takes therapeutic-range acetaminophen, then presents with aminotransferases often over five thousand, a normal or modestly raised bilirubin, and synthetic dysfunction. Aminotransferases over five thousand mean acetaminophen or ischemia, and he's had no hypotension. Injury appears in the blood at twenty-four to seventy-two hours, peaks at seventy-two to ninety-six, and then either recovers or progresses to acute liver failure, and he's at the peak.

25:24His low level doesn't reassure, because the nomogram doesn't apply to him. The Rumack-Matthew nomogram plots the level against time after a single ingestion on a log scale, with the United States treatment line running from one hundred fifty micrograms per milliliter at four hours to four point seven at twenty-four hours, and a level above the line between four and twenty-four hours means N-acetylcysteine. It doesn't apply to chronic supratherapeutic ingestion, to ingestion more than twenty-four hours earlier, to extended-release formulations, or to an unknown ingestion time, and in those settings the threshold for empiric treatment is low. His ingestion was chronic, so his low level only reflects drug already metabolized.

26:05He needs N-acetylcysteine now. It's a glutathione precursor, it conjugates NAPQI directly, and it has anti-inflammatory and microcirculatory effects late after ingestion, which likely explain its benefit in late presenters. It's indicated for a level above the line four to twenty-four hours after an acute ingestion, for high suspicion whatever the level, for chronic supratherapeutic ingestion, for an unknown ingestion time, for an existing rise in aminotransferases or coagulopathy, and for any acute liver failure of indeterminate cause. He starts intravenous N-acetylcysteine in the emergency department.

26:44The intravenous regimen is one hundred fifty milligrams per kilogram over sixty minutes, slowed from fifteen minutes to reduce anaphylactoid reactions, then fifty milligrams per kilogram over four hours, then one hundred milligrams per kilogram over sixteen hours, for three hundred milligrams per kilogram over twenty-one hours. It continues at one hundred milligrams per kilogram over sixteen hours, repeated, while encephalopathy, coagulopathy with an INR over about one and a half to two, or raised aminotransferases persist, or until transplant. The older oral protocol, one hundred forty milligrams per kilogram and then seventy every four hours for seventeen doses, is used less because it's longer and unpalatable.

27:25At twenty-one hours he's still encephalopathic, with an INR above three, so his infusion continues. In the United States registry, mortality from acetaminophen acute liver failure was under one percent when N-acetylcysteine started within twelve hours and rose steeply with each day of delay, so it starts the moment the diagnosis is suspected. He's transferred to a transplant center, and episode two covers the transplant criteria.

27:51The last patient shows the setting where the nomogram does apply. A nineteen-year-old woman took forty five-hundred-milligram tablets, twenty grams, two hours ago after an argument. She's alert and mildly nauseated, with normal aminotransferases. Activated charcoal, one gram per kilogram by mouth, is given within one to four hours in a cooperative patient with a protected airway, and it's most effective in the first hour. It isn't given to a patient who's obtunded without a protected airway, at risk of aspiration, or with a co-ingestant that rules it out, and it doesn't interfere with N-acetylcysteine. She drinks it. Her four-hour level is two hundred forty, above the line of one hundred fifty, so she starts N-acetylcysteine. Her aminotransferases stay normal, and the course stops at twenty-one hours.

28:40Her normal tests on arrival show why early appearances mislead. Phase one, the first twenty-four hours, brings nausea, vomiting, malaise, and sweating with normal aminotransferases, and patients can look well. Phase two, at twenty-four to seventy-two hours, brings rising aminotransferases, right upper quadrant pain, an enlarged liver, and developing coagulopathy. Phase three, at seventy-two to ninety-six hours, is the peak, with aminotransferases often over ten thousand, peak bilirubin and INR, jaundice, encephalopathy, and in fulminant cases acute liver failure, sometimes with kidney failure from NAPQI. Phase four, from day four, is recovery over one to two weeks without chronic damage.

29:26Here are the traps the boards set in these patients. Supplements belong in every history. Idiosyncratic injury usually takes one to three months, not days. Cirrhosis doesn't raise the risk of drug injury, but it makes injury more dangerous. Hy's law is checked at presentation. Autoimmune-like drug injury isn't idiopathic disease, and it doesn't need lifelong treatment. Routine drug injury doesn't get steroids. Weight-loss supplements are more dangerous than bodybuilding ones. And HLA-B star fifty-seven oh one is tested before abacavir.

29:57The mechanism traps follow. Rifampin, slow acetylation, and alcohol amplify isoniazid injury, and isoniazid doesn't continue through jaundice. Valproate can cause dangerous hyperammonemia with only modest aminotransferases. Methotrexate isn't monitored by ALT alone. Statins aren't withheld in fatty liver disease. And amiodarone injury isn't alcoholic hepatitis.

30:23The biopsy traps come next. Amoxicillin-clavulanate isn't excused because the course ended weeks ago. A rash weeks after a drug was started can be DRESS. Granulomas aren't blamed on a drug until sarcoidosis and infection are excluded. And herbal teas are a cause of sinusoidal obstruction syndrome that patients don't think to mention.

30:42The acetaminophen traps close the list. Four grams a day isn't always safe in a fasting drinker. The nomogram doesn't apply to chronic, late, extended-release, or unknown-time ingestion, and a low level doesn't reassure in those settings. N-acetylcysteine doesn't wait for a level, and it doesn't stop at twenty-one hours while injury persists. And a patient who looks well in the first day can still be poisoned.

31:06So, start to finish. Suspect drug injury with any new abnormality in the liver tests, and take a complete history, supplements included. Apply Hy's law at presentation, use R for the pattern, and judge causality by timing, dechallenge, and exclusion. Autoimmune-like injury remits after the drug stops, and supplements outside bodybuilding carry the highest transplant rate.

31:29Injury follows when phase one outruns phase two. CYP2E1 induction and glutathione depletion lower the toxic dose of acetaminophen, and isoniazid injury is worst over fifty, with alcohol or rifampin, and in the first three months. Valproate poisons mitochondria, methotrexate causes cumulative fibrosis, statins are safe in fatty liver, and amiodarone mimics alcoholic liver disease.

31:56Read the biopsy with the history: zone three necrosis for acetaminophen, bland cholestasis weeks after amoxicillin-clavulanate with a risk of vanishing bile ducts, DRESS from phenytoin, granulomas only after excluding infection, microvesicular steatosis for mitochondrial failure, and sinusoidal obstruction after herbal teas or myeloablation.

32:16For acetaminophen, use the nomogram only for a single, timed, acute ingestion. Otherwise give N-acetylcysteine, one hundred fifty milligrams per kilogram over an hour, fifty over four hours, then one hundred over sixteen hours, continued while injury persists, and don't wait for a level.

32:35Episode two is acute liver failure: the definition and causes, the intensive care unit, ICU, care that targets cerebral edema, the causes with specific treatments, and who needs a transplant.

32:48For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of two of chapter nineteen, and I'll see you in the next one.