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25 Cards in this Set
- Front
- Back
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Inherited causes of cirrhosis: infants and children vs adults
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Infants and children:
-alpha1-antitrypsin -familial intrahepatic cholestasis -other Adults -hemochromatosis Increased penetrance) -alpha1-antitrypsin |
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Hemochromatosis and iron overolad disease: overview, pathogenesis, genetic cause, secondary causes
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Distinguishing features
-Hereditary -Early and progressive expansion of the plasma iron compartment -Progressive parenchymal iron deposition that can cause severe damage and disease to liver, endocrine glands, heart, and joints -Nonimpaired erythropoiesis and optimal response to therapeutic phlebotomy -Defective hepcidin synthesis or activity Pathogenic basis -Mutations leading to inappropriately low levels of hepcidin activity Genetic cause -HFE mutation Secondary causes -Alcoholic liver disease -Chronic HBV, HCV -NASH |
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Iron homeostasis
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Ingest ~10-20 mg/day in our diet
Intestine absorbs ~1-2 mg/day Iron is transported by Transferrin in blood; iron is stored in cells bound to Ferritin Body content of iron ~ 4 g; ~ 1 g is stored in hepatocytes ~ 20 mg/day is delivered to the bone marrow for incorporation into hemoglobin of erythroid precursors & mature red cells ~ 20 mg/day is derived from macrophage destruction of senescent red cells ~1-2 mg/day are lost from the iron pool ~ 30 mg/month is lost in Menses |
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Genetics of hereditary hemochromatosis
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Mutations in the HFE gene are responsible for most cases of HH
Autosomal recessive 2 major mutations: -Cysteine 282->tyrosine (C282Y) -Histidine 63->aspartic acid (H63D) C282Y homozygosity produces major clinical manifestations Highly prevalent in individuals of Northern European descent, rare in Africa and Asia; frequency of C282Y homozygotes is ~1/250 for Anglo-Celic-Nordic population. 10-20% who are homozygous progress on to develop iron overload disease |
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Mechanism of hereditary hemochromatosis
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Normal
-Iron absorbed from intestine -Transported by ferroportin to circulation and associates with transferrin -Goes to liver -Sensor associated with transferin, HFE, and HJV which initiates a signalling pathway which tells liver to produce hepcidin -When there is a lot of iron coming in, liver turns on production of hepcidin -Hepcidin shuts down uptake of iron by inhibiting ferroportin (in enterocytes and macrophages) -Plasma levels of iron drop and liver levels of iron maintain homeostasis Hemochromatosis -Mutant HFE -Iron comes to liver, but signalling pathway doesn't begin -Liver is blind to iron and doesn't produce hepcidin -Over time, uncontrolled iron absorption and release manifests as disease Hemochromatosis is caused by reduced hepatic release (or activity) of hepcidin (too little) Too much hepcidin is bad too (blocks absorption of iron from GI tract and causes anemia) |
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Natural history of hereditary hemochromatosis
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Age 10: increased serum iron
Age 15: increased hepatic iron Age 30: tissue injury Age 40: cirrhosis, organ failure Typically seen in males in their 40’s-50’s and females in their 60’s (curve is shifted in women as a result of iron loss due to menses & childbirth) |
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Symptoms and physical findings in hereditary hemochromatosis
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Symptoms:
-Most patients are asymptomatic when they are discovered by genetic screening, family member, abnormal LFTs or iron panel -Nonspecific: weakness, fatigue, lethargy Physical findings: -Hepatomegaly -Liver failure: ascites, encephalopathy -Joints: arthritis, joint swelling -Heart: dilated cardiomyopathy, CHF -Skin: increased pigmentation -Endocrine: testicular atrophy, hypogonadism, hypothyroidism The classic triad of cirrhosis, diabetes, and skin pigmentation (“bronzed diabetes”) is rare now due to increased awareness of HH and earlier diagnosis and treatment |
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Diagnosis of hereditary hemochromatosis
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Genetic testing if there is a family member
Transferrin saturation = (Serum iron/TIBC)*100 -Elevated Serum ferritin -Elevated Liver biopsy is performed solely to assess damage in HH patients (not for diagnosis) Hepatic Iron index = amount of iron (µmoles) per g liver (dry weight) ÷ age (in years) |
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Treatment, monitoring, and maintenance of hereditary hemochromatosis
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Treatment
Perform phlebotomy of 500 mL (1 unit) of whole blood weekly until hematocrit value drops below 37%. ( 1 unit ~ 200-250 mg iron) The iron-chelating drug deferoxamine can be used in those patients who cannot tolerate phlebotomy. Monitoring Check transferrin saturation and ferritin levels at 2- to 3-month intervals to monitor response (optional). Maintenance Once iron stores are depleted (serum ferritin <50 ng/mL; transferrin saturation <50%), proceed to maintenance phlebotomy of 1 unit of whole blood every 2 to 3 months. Aim to keep transferrin saturation <50%; if successful, ferritin should remain <50 ng/mL. |
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Results of treatment of hereditary hemochromatosis
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Results of Phlebotomy – Can restore normal life expectancy if diagnosed early
Preventable: All clinical manifestations Reversible: Cardiac dysfunction, glucose intolerance, hepatomegaly, skin pigmentation Irreversible: Cirrhosis, arthropathy, hypogonadism, risk of hepatocellular carcinoma |
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Alpha1-AT disease: summary
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Common inherited metabolic disease causing lung + liver disease
Most common genetic cause of liver disease in children Prevalence of deficiency allele combinations ~ 1:490 (North America); severe deficiency ~1:3500 live births (more common in Caucasians; rarely found in African Americans or Asians) Autosomal recessive disease Caused by mutations in α1-antitrypsin gene (SERPINA1) α1-AT binds and inactivates neutrophil elastase and other serine proteases; a1-AT is the major serine protease inhibitor in blood α1-AT alleles are also called Protease inhibitor (Pi) alleles. Most common Pi alleles associated with disease: PiZ, PiS |
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Alpha1-AT disease: mechanism of disease
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A defect in protein folding
Mechanisms of lung and liver injury are distinct Absence of α1-AT is the primary mechanism for premature development of pulmonary emphysema or COPD in the affected patients (“loss of function”) Liver disease is caused by accumulation of misfolded α1-AT protein (“gain of function”) – “PiZZ” Mutations cause the α1-AT protein to polymerize in the ER of hepatocytes |
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Alpha1-AT disease: clinical presentation
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Common genetic cause of liver disease in neonates and children
Clinical presentation is variable - Children often 1st present with jaundice - Adults usually present with cryptogenic cirrhosis with portal hypertension Distinct biomodal distribution for clinical presentation – - Neonatal hepatitis/ cholestatic jaundice in infants - Chronic liver disease in adults (mean age of diagnosis 5th decade) ~10% of PiZZ children develop neonatal hepatitis; ~2% progress to advanced fibrosis or cirrhosis requiring transplantation ~10-20% of adult PiZZ patients develop cirrhosis; |
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Alpha1-AT disease: diagnosis
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Protease inhibitor (Pi) alleles distinguished by isoelectric focusing or molecular genotyping
-Z allele associated with liver disease Risk of pulmonary emphysema rises when serum α1-AT drops below ~ 11 µM Serum α1-AT levels do not strictly correlate with risk of liver disease Disease phenotype is defined by the serum levels (lungs) and alleles (liver, two copies of Z) Liver disease is associated with PiZ allele (lysine to glutamic acid at AA342) Liver biopsy can be obtained to confirm the diagnosis, but is not required Periodic acid-Schiff (PAS)-positive “globules” are common in PiZZ alpha1-antitrypsin disease, but can be found in other liver diseases |
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Alpha1-AT disease: treatment
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No specific therapy is currently available (avoid alcohol, smoking, weight gain and obesity)
Treatment of complications of liver and lung disease Hepatocellular carcinoma surveillance Transplantation (cures the liver and lung disease) α1-AT infusions (treats the lung disease - emphysema) Family screening |
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Wilson disease: overview
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Rare inherited metabolic, copper accumulation in liver and brain
Prevalence ~ 1:30,000 (carrier state 1: 90) Autosomal recessive disease caused by mutation in ATP7B gene (> 300 mutations) Defective biliary excretion of copper; copper overload affects multiple organs Commonly presents with liver or neurological symptoms Variable age of onset for symptoms (usually 6 - 40 years of age) Undiagnosed and untreated is generally fatal by age 30 Early diagnosis and treatment can yield almost complete recovery with normal life Treated with chelating agents or zinc (rarely with liver transplantation) |
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Wilson disease: overview of copper metabolism
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Essential nutrient. Copper is an essential cofactor for many enzymes, including Cytochrome-c oxidase, superoxide dismutase, Catechol oxidase, Protein-lysine 6-oxidase, Ceruloplasmin, Dopamine-α-monooxygenase
Dietary Sources: oysters, liver, crab, shrimp, cod, yeast, olives, hazelnuts, whole wheat bread, peas RDA: 0.9 mg Daily Intake (Western diet): 4-6 mg Absorption: 40-60% efficiency Transport in Blood: ceruloplasmin (>95%), albumin (<5%) Storage: Liver (regulated) Excretion: Bile (major route), urine (minor route) |
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Wilson disease: defect
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Defect in hepatic copper transport into blood and bile
Copper absorbed and carried by albumin to liver Block in liver's ability to secrete copper into bile and plasma (associated with ceruloplasmin) -Defect in ATP7B copper transporter Copper accumulates in liver Binds to albumin and carried to other tissues |
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Wilson disease: presentation
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Liver
Abnormal liver function tests Acute hepatitis Acute hepatic failure Liver disease with hemolysis Chronic hepatitis Cryptogenic cirrhosis CNS Parkinson-like disorders dystonia, tremors Psychiatric disorders Eye Kayser-Fleischer rings (95% of patients with neurologic signs and 40-60% with hepatic presentation will show KF rings. KF rings by themselves not specific for WD) Sunflower cataracts Kidney Fanconi syndrome with hypouricemia Bone/joint Osteopenia Arthropathy Initial presentation -40% liver disease (patients < 30 y) -35% neurological (wide age range) -15% psychiatric (wide age range) -10% endocrine, renal, cardiac, hematological |
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Wilson disease: diagnosis
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Unexplained Liver Disease or Neuropsychiatric Disorder + Liver Disease
- Measure serum ceruloplasmin (< 20 mg/dL) - Measure serum free copper (> 25 mcg/dL) - Measure 24 h urinary Copper excretion (> 40 mcg) - Slit lamp exam (Kayser-Fleischer rings) - (Liver biopsy for histology or quantitative copper measurements) |
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Wilson disease: therapy, monitoring, results
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Therapy:
Chelation (Penicillamine or trientine) plus pyridoxine Zinc (block absorption of copper) Avoid high copper foods (diet alone is ineffective) Liver transplantation (with acute liver failure or end-stage liver disease) Monitoring: Kayser-Fleischer rings Urinary copper excretion Serum free copper levels (non-ceruloplasmin-bound) Results: Prevents disease when begun early Improves liver and CNS disease Prolongs life Therapy is lifelong, patients who stop chelation therapy have poor prognosis. Sudden interruption of therapy can result in acute liver failure |
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Nonalcoholic fatty liver disease: common causes
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NAFLD is a common cause of elevated
liver enzymes and includes: ~ 90% of morbidly obese patients ~80% of patients with T2 diabetes ~30% of adults in the US NAFLD=>NASH=>Cirrhosis=>Carcinoma - NAFLD can progress to Nonalcoholic Steatohepatitis (NASH) - ~ 20% of patients with NASH may progress to Cirrhosis and increased risk of hepatocellular carcinoma (HCC) |
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Nonalcoholic fatty liver disease: presentation
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Asymptomatic when they present
Elevation of ALT and AST -AST/ALT ratio <1 |
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Nonalcoholic fatty liver disease: diagnosis
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Individuals with metabolic risk factors (diabetes and obesity)
Exclude excessive alcohol use and other forms of liver disease by history and lab tests Image liver with US, CT, or MRI If liver normal -Liver biopsy If fatty liver present -Consider liver biopsy to stage disease and define risk of progression |
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Nonalcoholic fatty liver disease: therapy
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Current therapy is largely restricted to
lifestyle modifications – dietary restriction, exercise No FDA-approved therapies |
