Metabolic LD

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    Nonalcoholic Fatty Liver Disease

    Introduction

    • aka. NAFLD
    • Ranges from:
      • Asymptomatic hepatic steatosis to cirrhosis.
    • Usually results from:
      • Insulin resistance
      • Metabolic Syndrome (obesity, DM, dyslipidemia, HTN).
    • Inflammation and fibrosis in NAFLD ==> nonalcoholic steatohepatitis (NASH)
    • Prevalence:
      • 30% NAFLD
      • 20% NASH
      • 10% Cirrhosis

    Diagnosis

    • NAFLD and NASH diagnosed after exclusion of other causes by serology.
    • Abdo U/S, CT, MRI: hepatic steatosis (hard to identify fibrosis/inflammation).
    • NASH is usually inferred in pts with metabolic syndrome + elevated enzymes w/o other causes.
    • Liver biopsy: Confirms NASH + classifies severity.  (No noninvasive indicators of fibrosis).
    • Three main features:
    1. Mild elevation of transaminases
    2. Risk Factors (diabetes, obesity, hyperlipidemia)
    3. Imaging consistent with hepatic steatosis

     

    Treatment

    • NAFLD, NASH: mainstay of treatment is weight loss and management of comorbidities.
    • Monitor liver enzymes + liver function tests q3-6mo.
    • Use of statins is indicated for dyslipidemia (NOT contraindicated in setting of NASH!!)
    • Anxioxidants and hypoglycemics (metformin, thiazolidinediones) assessed in trials = did not improve outcomes.

    Hereditary Hemochromatosis

    • Condition in which there is a dysregulation of iron absorption leading to iron overload causing multi-organ toxicity.
    • Most common genetic disorder in white patients.
    • Normal Iron absorption: 1-2mg
    • Most people with elevated Ferritin and transferrin saturation do not have hemochromatosis.  (Acute phase reactant)
    • Symptoms:
      • Vascular: Erectile dysfunction
      • Cardiac: Dilated cardiomyopathy, Heart Failure, atheroscerosis
      • Skin: Hyperpigmentation
      • Endocrine:
        • Diabetes Type II ("bronse diabetes")
        • Hypothyroidism
        • Hypogonadism
      • MSK: arthropathy - joint pains (Usually 2nd and 3rd MCPs of hands).
    • Extrahepatic Manifestations:
      • Diabetes ("Bronze diabetes")
        • Pigmentation of skin
        • Endocrinopathy (Diabetes)
      • Heart failure (Cardiomyopathy, Arrhythmias)
      • Arthropathy
      • Skin Color Changes.
    • Diagnosis:
      • Patients with unexplained transaminase elevation should be tested.
      • First line (screen): 
        • Ferritin (>1000 in absence of inflammatory state) AND
        • Transferrin saturation (>45%) [Iron / TIBC)
      • MANY reasons for high ferritin and Transferrin satutation (i.e. acute inflammatory states), but if suspicion is high, can do HFE gene testing.
      • Second Line (confirming): HFE gene testing.
        • Not everyone with homozygous HFE gene will have hemochromatosis (70% will have high iron)
          • (autosomal recessive, and 70% penetrance).
          • Most highly predictive mutation is the c282y (homozygous).
        • Few of those with hemochromatosis get cirrhosis (10%)
      • Liver biopsy can also confirm diagnosis, and usually done to determine if cirrhosis.  (If RF's for cirrhosis: Age > 45, ferritin > 1000)
        • (if positive need HCC surveillance, and varices screening)
    • Treatment:
      • Liver biposy is key to check for cirrhosis (if >45yo, ferritin > 1000)
        • If symptomatic or organ failure:  Treat
        • If asymptomatic/ no organ failure/ no cirrhosis: Can observe, but annual close f/U
          (will likely require treatment eventually, many start phlebotomy early)
      • Phlebotomy!
        • Highly effective!
        • Daily for a period of time until ferritin drops to normal, then q6mo -1year (varies).
          • Usually ferritin 50-100 is targeted.
        • Can donate extra blood (not used in the past because "diseased", but now used as normal blood).
          • However, have to pay for the procedure if know the diagnosis
            (In US: cannot "donate" for free, but can pay and donate)
        • Outcomes:
          • HIGHLY EFFECTIVE, Stops progression of cirrhosis
          • Somehow erectile dysfunction and arthopathy do not imrove with treatment
        • No vitamin C during ferritin reduction therapy.
          • (Causes increased reactive oxygen species (ROS), causing more organ damage).
        • Dietary changes: no difference.
      • Iron Chelation Therapy
        • Indicated only if cannot tolerate phlebotomy (Chelation therapy very expensive).
        • Deferoxamine - Iron chelator, IV/SC forms only.
        • New oral agent in US.
      • Screen 1st degree relatives

    Secondary Iron Overload

    • Typical conditions at risk:
      • Thalassemia (iron readily absorbed)
      • Extensive transfusions (extensive transfusions)
        • Myelodysplasia
    • Treatment:
      • Chelation (rather than phlebotomy, b/c they are anemic).
        • Deferoxamine (IV)
          • Used historically, IV only.
        • Deferasirox (Oral)
          • Used now, easier, well tolerated
          • Rare Side Effects: Agranulocytosis (serious), renal failure.

    Alpha-1-Antitrypsin Deficiency

    • Conformational protein disorder --> causing hepatic accumulation of variant protein inclusions.
      • Hepatic A1AT protein overload (inclusions) --> liver cirrhosis from variant protein inclusions.
      • Pulmonary A1AT deficiency --> panacinar emphysema (liver sequesters all A1AT causing unchecked proteolysis)
        • Risk factors: age, smoking, other lung disease.
    • High risk of cirrhosis and HCC.
    • Management:
      • No specific treatment for liver disease.
      • Consider transplant if liver failure develops.
      • Occasional PFTs for obstructive disease.
        • If develops lung disease --> give IV alpha-1-antitrypsin. (does not help liver disease)

     

    Wilson Disease

    • Audosomal recessive disorder of copper transport.
      • Decreased hepatic uptake and decrease biliary excretion of copper.
    • Very rare!
    • Affects 1 in 30,000 newborns, usually diagnosed <45yo.
    • Clinical Features:
      • Often present in fulminant hepatic failure
        • Abnormal liver enzymes
        • Hemolytic anemia
        • Normal or decreased serum ALP level (interferes with synthesis)
      • Fulminant wilson liver disease is FATAL without an urgent transplant.  NEED EARLY REFERRAL
      • Always exclude in young patients with abnormal liver chemistry. (often <45yo)
    • Diagnosis:
      • Screening: Serum ceruloplasmin (reduced!)
      • Follow up with: Urine copper (increased!)
      • Confirm diagnosis with liver biopsy!
    • Extrahepatic Manifestations:
      • Neuropsychiatric abnormalities **common (deposition of copper in brain)
      • Kayser-Fleischer rings on ophthalmologic examination (copper deposition in Descemet membrane of cornea)
    • Treatment:
      • Copper chelating agents (trientine, penicillamine)
      • Lower copper diet.
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