Inherited Liver Diseases: Inherited Liver Diseases: Wilson Disease

0:00Welcome to Board Pearls. This is episode two of three of the Inherited Liver Diseases chapter, in the Liver Disease module. This episode is Wilson disease, from diagnosis to lifelong treatment. A teenager with a raised alanine aminotransferase, ALT, and a new tremor shows what the defective gene does, why ceruloplasmin is low, who to suspect and at what ages, and how the Leipzig score combines five features into a diagnosis. A young man with steatohepatitis and borderline results shows why ceruloplasmin can't decide alone, which results exclude the disease, and when genetic testing is needed, and the teenager's brother shows why every sibling is screened. A young woman on trientine who wants to become pregnant shows why trientine is preferred over penicillamine, what has to be kept away from it, where zinc fits, how to read the twenty-four-hour urine copper on each drug, and how pregnancy and contraception are handled. And a man who stopped his treatment shows when transplant is the answer.

0:59Here's the first patient. A seventeen-year-old girl has had a raised ALT for a year, labeled probable fatty liver disease, though her body mass index, BMI, is twenty-one. Over three months her grades have fallen and her handwriting has become shaky. Her mother says she's moody and drools at night. Her ALT is one hundred ten.

1:18Unexplained liver disease in a lean teenager, now with tremor, drooling, and falling grades, is Wilson disease until proven otherwise. Wilson disease is inherited copper overload from a failed copper pump. It comes from mutations in ATP7B on chromosome thirteen. More than five hundred have been described, about three hundred eighty of them disease-associated, and H1069Q is the most common in people of European descent. Most patients are compound heterozygotes, with two different mutations, rather than true homozygotes. The disease is rare, about one in thirty thousand to one hundred thousand, with a carrier rate of about one in ninety.

1:59The pump's two jobs explain the two hallmarks. ATP7B is a copper-transporting ATPase in the hepatocyte's trans-Golgi. It pumps copper into the bile canaliculus for excretion, and it loads copper onto apoceruloplasmin. When it fails, biliary copper excretion collapses and copper accumulates in the liver, and apoceruloplasmin is left empty. Empty apoceruloplasmin has a much shorter half-life in the circulation, which is why the serum ceruloplasmin is low.

2:29How copper does damage explains why her liver came first and her brain second. Copper injures tissue through free radicals, glutathione depletion, and lipid peroxidation of mitochondrial membranes, which explains the steatosis, the mitochondrial injury, and, when copper is released suddenly, a Coombs-negative hemolysis. Copper builds up first in the liver, then spills into the blood as free copper, not bound to ceruloplasmin, and deposits in the brain, the kidney, the red cells, and the cornea, where Kayser-Fleischer rings are copper at Descemet membrane. The mean age at presentation is ten to fourteen for liver disease and nineteen to twenty-two for neurologic disease, so liver injury can come up to a decade before neuropsychiatric symptoms. That's why Wilson disease is considered in anyone aged about three to forty-five, and rarely older, with unexplained liver disease.

3:21Her liver presentation was the easy one to miss. Liver disease is the first presentation in about forty percent, ranging from an asymptomatic rise in aminotransferases to chronic hepatitis, cirrhosis at a young age, and fulminant failure with Coombs-negative hemolysis. Liver cancer is rare despite advanced fibrosis, unlike hemochromatosis and most other chronic liver diseases. Wilson disease is often misdiagnosed as metabolic dysfunction-associated steatotic liver disease, MASLD, especially in young patients without metabolic syndrome, because the biopsy shows steatosis, glycogenated hepatocyte nuclei, and Mallory hyaline that overlap with alcohol and metabolic dysfunction-associated steatohepatitis, MASH. So a young patient with steatohepatitis and no insulin resistance gets a Wilson workup before MASLD is accepted. Her MASLD label needed a cardiometabolic criterion she never had.

4:22Her new symptoms are the neuropsychiatric presentation. It includes tremor, especially the wing-beating tremor with the arms abducted and the elbows flexed, along with stiffness, choreoathetosis, parkinsonian features, dysarthria, drooling, and an abnormal gait, and also depression, mood disorder, or a change in personality. In children, the first sign may be poor school performance or behavior problems, as hers was. The highest-suspicion presentations are liver disease with new neurologic or psychiatric symptoms, which is hers, and acute hepatitis with Coombs-negative hemolysis.

4:58Copper reaches other organs too. In the renal tubule it causes distal renal tubular acidosis, hypercalciuria with stones, and Fanconi syndrome, with aminoaciduria, glucosuria, phosphaturia, and a low uric acid. Sunflower cataracts, copper in the lens capsule, are a second eye finding. Polyarthritis, early osteopenia, arrhythmias, heart failure, glucose intolerance, and menstrual problems also occur.

5:27Her diagnosis needs at least two of five features. They are Kayser-Fleischer rings on slit lamp; a ceruloplasmin under twenty milligrams per deciliter; typical neurologic symptoms; a twenty-four-hour urine copper over forty micrograms a day, though most symptomatic patients exceed one hundred; and a hepatic copper over two hundred fifty micrograms per gram of dry weight. The Leipzig score combines them. A score of four or more establishes the diagnosis, three makes it possible and calls for further testing, and two or less makes it unlikely. The score underpins the twenty twenty-three American Association for the Study of Liver Diseases, AASLD, practice guidance, which has separate branches for patients with and without rings.

6:12She has rings, a ceruloplasmin of eight, a urine copper of two hundred twenty, and neurologic signs. That's four features, diagnostic without a biopsy. Testing her ceruloplasmin, urine copper, and eyes at her first unexplained ALT could have found the disease while it was still confined to her liver.

6:31The second patient shows why ceruloplasmin can't decide alone. A twenty-four-year-old man with a BMI of twenty-two and no metabolic risk factors has steatohepatitis on biopsy, a ceruloplasmin of eighteen, a normal slit lamp, a urine copper of sixty, and no neurologic signs. Young, lean, and without insulin resistance, he needs a Wilson workup. A low ceruloplasmin alone has a positive predictive value of only about six percent, because it's also low in malabsorption, protein-losing enteropathy, synthetic failure from any acute liver failure, ATP7B heterozygotes, Menkes disease, dietary copper deficiency, and cervical dystonia. And a normal ceruloplasmin leaves a negative predictive value of only about twenty-five percent. Serum free copper, estimated as total copper minus three point one five times the ceruloplasmin, is over twenty-five micrograms per deciliter in symptomatic disease.

7:28His results put him in the possible range. His ceruloplasmin is just under twenty, his urine copper is over forty but well under one hundred, and he has no rings. His absent rings don't exclude anything, because Kayser-Fleischer rings are present in the large majority of patients with psychiatric or neurologic disease but in only about half to sixty percent of those with liver disease alone.

7:50His next step is the liver copper, and a few results settle the question outright. A ceruloplasmin over thirty essentially excludes Wilson disease, and a hepatic copper under thirty-five micrograms per gram excludes it. Quantitative hepatic copper, measured spectrophotometrically in homogenized tissue, is the gold standard. The rhodanine stain is neither sensitive nor specific, because copper is unevenly distributed. Electron microscopy, when it's available, shows abnormal mitochondria with widened intracristal spaces and dilated cristae tips, which is highly specific when present.

8:26A hepatic copper of fifty to two hundred fifty is intermediate, neither confirming nor excluding the disease, because treated or partly compensated disease can sit in that range, and it calls for ATP7B genetic testing. His tissue copper is one hundred forty micrograms per gram, intermediate, and ATP7B testing finds two disease-causing mutations.

8:48The first patient's diagnosis reaches her family. Inheritance is autosomal recessive, so each sibling has a twenty-five percent risk and is screened with a ceruloplasmin, a slit-lamp exam, and ATP7B testing when the proband's mutations are known or the first screens are equivocal. Her twelve-year-old brother feels fine and does well in school, but he carries both her mutations and has a normal exam. He has presymptomatic Wilson disease, and he's treated before his liver or brain is injured.

9:16Every patient diagnosed will be on treatment for life, and the third patient shows what seven years of it looks like. A twenty-six-year-old woman was diagnosed at nineteen with liver involvement and a mild tremor, and she's taken trientine since. She takes an iron supplement with her morning dose for heavy periods, and she's on an estrogen-containing pill. She wants to become pregnant next year and asks whether she'll have to stop her medicine.

9:40She won't stop. What needs attention is her habits around the drug. Symptomatic Wilson disease is treated with a chelator, with zinc for maintenance and a low-copper diet that avoids shellfish, organ meats, nuts, chocolate, and mushrooms. Trientine is the first-line chelator. It's better tolerated than D-penicillamine and far less likely to cause paradoxical neurologic worsening, which occurs with penicillamine in up to half of patients. Both drugs excrete copper in the urine, but penicillamine pulls copper out of peripheral tissues, including the brain, more aggressively, sometimes transiently raising the brain's copper, while trientine produces a slower, more controlled exit. So trientine is the starting drug for neurologic disease and whenever neurologic worsening would be intolerable, as it would have been with her tremor. Its dose is seven hundred fifty to fifteen hundred milligrams a day in two or three divided doses on an empty stomach, with seven hundred fifty to one thousand for maintenance.

10:35Her morning iron is a problem because of what trientine binds. Trientine chelates oral iron into a toxic complex, so iron is never taken with it, and her iron moves well away from her trientine. It also chelates zinc, so the two are separated by at least an hour. And overtreatment causes a reversible sideroblastic anemia, because copper is needed for ferrochelatase in heme synthesis, so an unexplained anemia on trientine means backing off the chelation, not giving more iron.

11:06Penicillamine is the older chelator she was spared. Its standard adult dose is one to two grams a day in four divided doses, at least thirty minutes before meals. Its side effects are skin rash, nephritic syndrome with proteinuria, hypersensitivity, immunosuppression, a lupus-like reaction, marrow toxicity, paradoxical neurologic worsening, and impaired wound healing from inhibition of lysyl oxidase, the enzyme that cross-links collagen. It needs pyridoxine, twenty-five to fifty milligrams a day, because its sulfhydryl group binds and depletes vitamin B6. Trientine doesn't need it.

11:46Zinc works differently, and it's what her brother takes. It's given at fifty milligrams three times a day as acetate, gluconate, or sulfate. It induces metallothionein in the enterocytes, which binds copper preferentially, and the bound copper is shed with the enterocyte into the stool, blocking absorption. About forty percent of patients have nausea, vomiting, or diarrhea, and zinc can raise liver tests by itself. It's used for maintenance after copper has been removed, and as monotherapy in presymptomatic patients like her brother. Its onset is slow and it doesn't mobilize copper, so it isn't adequate for symptomatic disease.

12:25Her adherence and her dose are judged by the twenty-four-hour urine copper, and the target depends on the drug. On a chelator, the goal is two hundred to five hundred micrograms a day. A value under two hundred means either non-adherence or overtreatment, and the free copper separates them. A free copper over fifteen micrograms per deciliter means non-adherence, with copper circulating but not being excreted, and under five means overtreatment, with little copper left to excrete. On zinc, the urine copper should be no more than seventy-five micrograms a day, because zinc blocks absorption rather than pushing copper into the urine, so a higher value suggests non-adherence or ongoing excess.

13:03Her urine copper is three hundred twenty on trientine, which is on target. A urine copper of one hundred twenty with a free copper of nineteen would mean she isn't taking her trientine, and lowering the dose would make her worse. A urine copper of one hundred fifty with a free copper of three and a new anemia would mean overtreatment, with sideroblastic anemia from copper depletion, treated by lowering the trientine, not with iron.

13:29Her pregnancy plan starts with one rule: therapy is never stopped, because stopping risks a maternal flare. The dose is reduced instead, typically to seven hundred fifty to one thousand milligrams of penicillamine or trientine in the first and second trimesters and five hundred milligrams a day in the third, roughly a quarter to a half lower. The fetus needs copper, and wound healing at delivery depends on copper-dependent lysyl oxidase. A woman on trientine may need more iron in pregnancy, because trientine binds iron while demand is rising, and that iron is still timed away from her trientine. Untreated Wilson disease commonly causes infertility through copper-mediated implantation failure, so adequate chelation before conception is itself a fertility treatment.

14:14Her child's risk depends on her partner. With a partner who isn't a carrier, the risk of an affected child is about half a percent, so haplotype analysis of the partner is recommended before pregnancy to refine that risk. Her partner tests negative.

14:30Her pill has to change. Estrogen-containing oral contraceptives interfere with biliary copper excretion and are avoided, and so are copper intrauterine devices, IUDs, which are a continuous local copper source, so she switches to a method without estrogen or copper. Many prenatal vitamins contain copper, so she uses one without copper or with confirmed low copper, and copper-containing supplements are avoided. Breastfeeding isn't recommended on penicillamine, and zinc alone is sometimes used after delivery if it maintains her adequately. She stays on trientine, reduced in her third trimester, and delivers a healthy daughter.

15:08The last patient shows what happens when treatment stops. A thirty-one-year-old man stopped his trientine a year ago and now has jaundice, ascites, and an international normalized ratio, INR, of two point eight. He has decompensated Wilson cirrhosis. Liver transplant cures the liver disease, because the donor liver carries working ATP7B and restores both biliary copper excretion and ceruloplasmin loading. It's the rescue for fulminant Wilson disease and for decompensated cirrhosis that has failed medical treatment, so he's referred. Treatment is lifelong, and stopping it is how controlled disease becomes a transplant.

15:44Transplant for isolated neurologic disease is a different question, and it's controversial. Neurologic disease doesn't reliably improve after transplant, and with a compensated liver the risks outweigh the benefits. In a multicenter cohort transplanted mainly for liver disease, patient and graft survival were excellent, but the patients with mainly neurologic disease showed minimal early neurologic recovery.

16:08Here are the traps the boards set in these patients. Fatty liver disease in a lean young patient isn't accepted without checking for Wilson disease. A low ceruloplasmin alone doesn't make the diagnosis, and a normal one under thirty doesn't exclude it. Absent Kayser-Fleischer rings don't rule it out. A rhodanine stain isn't reliable. An intermediate liver copper calls for genetic testing. Neurologic symptoms can arrive a decade after the liver disease. And every sibling is screened.

16:36The treatment traps follow. Penicillamine isn't the first choice in neurologic disease, and when it's used it needs pyridoxine. Iron and zinc are never taken together with trientine. An anemia from overtreatment isn't treated with iron. Zinc alone isn't enough for symptomatic disease. A low urine copper on a chelator is read with the free copper, and zinc's urine copper target is different from a chelator's. Therapy is never stopped in pregnancy. Estrogen contraceptives and copper IUDs are avoided. And transplant isn't done for neurologic disease alone.

17:09So, start to finish. Consider Wilson disease in anyone about three to forty-five with unexplained liver disease, especially when it looks like MASLD without metabolic risk or comes with neuropsychiatric symptoms. ATP7B failure blocks biliary copper excretion and leaves ceruloplasmin low. Combine Kayser-Fleischer rings, a ceruloplasmin under twenty, a urine copper over forty, neurologic signs, and a hepatic copper over two hundred fifty in the Leipzig score, where four or more is diagnostic, and use ATP7B testing for intermediate results. A ceruloplasmin over thirty or a hepatic copper under thirty-five nearly excludes it. Screen every sibling.

17:55Treat symptomatic disease with a chelator, trientine first, giving pyridoxine with penicillamine and keeping iron and zinc away from trientine. Use zinc for maintenance or for presymptomatic siblings. Target a urine copper of two hundred to five hundred on a chelator and seventy-five or less on zinc, reading a low chelator value by the free copper. Never stop therapy in pregnancy, reduce the dose in the third trimester, and avoid estrogen contraceptives, copper IUDs, and copper-containing vitamins. Transplant cures the liver disease but not reliably the neurologic disease.

18:29Episode three is the other inherited liver diseases: alpha-one antitrypsin deficiency, cystic fibrosis liver disease, polycystic liver disease, and the inherited cholestatic syndromes.

18:40For 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 two of three of chapter twenty-two, and I'll see you in the next one.