Why Some Genetic Mutations May Be Helpful: HFE

When one looks at diseases, it is important to consider that the mutations that cause the disease may confer other selective advantages.

A classic example has been sickle-cell disease.  The heterozygous state is usually asymptomatic and makes an individual less prone to malaria.  “In the USA, where there is no endemic malaria, the prevalence of sickle-cell anaemia among blacks is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and will tend to be selected out of the affected population via natural selection.” —Sicklecell disease – Wikipedia, the free encyclopedia

Another common disorder is hemochromatosis.  A recent letter in the New England Journal of Medicine (NEJM 2013; 369: 785-6) explains why having the HFE gene could be advantageous.  According to the authors the genetic mutation arose in Celtic populations who were notably taller than other populations.  As such, the authors hypothesized that the patients with HFE hemochromatosis would have better growth by having an abundant supply of iron during periods of rapid development.

They assessed a cohort of 176 Swiss patients with HFE hemochromatosis.  93% were homozygous for the C282Y mutation, 7% had a compound H63D-C282Y mutation.  All of the patients had verified iron overload determined as a ferritin > 300 mcg/L or a transferrin saturation >45%.

Compared with an age-matched, sex-matched Swiss reference population, men with hemochromatosis (n=120) were 4.3 cm taller on average. In women (n=56), the difference was 3.3 cm.  To avoid bias due to population origin, the cohort was also compared with data from Ireland where the data remained validated.

Take-home message: Extra iron in the first two decades of life promote better growth (and probably other advantages).  However, iron overload later in life can lead to cirrhosis, diabetes, heart disease, and reproductive problems.

Related blog post:

AASLD Hemochromatosis Guidelines:

Practice guidelines and 93 OLTx recommendations

While checklists have a role (Checklists for Crisis and Daily Care | gutsandgrowth), most will not be workable if each has 93 recommendations like the 2012 AASLD Adult Liver Transplant Practice Guidelines (Liver Transplantation 2013; 19: 3-26).

While the guidelines are comprehensive including topics like vascular thrombosis, immunosuppression, late rejection, bone health, kidney diseases, metabolic syndrome, reproductive health, and infectious disease, they are not easily organized.  Some recommendations include the following:

  1. “the frequency of monitoring with liver tests should be individualized by the transplant center (grade 1, level a)”
  2. “depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, ERCP, and ultrasound may be appropriate (grade 1, level a)”
  3. “frequent handwashing reduces the risk of infection…(grade 1, level a)”
  4. “shoes, socks, long-sleeve shirts and long pants should be worn for activities that will involve soil exposure..(grade 1, level a)”
  5. Patients “with PSC and inflammatory bowel disease…should undergo an annual screening colonoscopy ..(grade 1, level b)”
  6. “the ideal immunosuppression for pregnancy is tacrolimus monotherapy”

Thus, the recommendations are sometimes almost worthless like #1-3, sometimes difficult to implement like #4, and sometimes specific like #5-6.


While not useful as a practical checklist for routine care, this guideline offers useful information on a broad range of problems for transplant recipients.

NAFLD Guidelines 2012

Given the pervasiveness of Non-alcoholic Fatty Liver Disease (NAFLD), updated practice guidelines are worth a look (Hepatology 2012; 55: 2005-23, also in Gastroenterology 2012; 142: 1592-1609)).  While the review includes updated information on incidence, prevalence, risk groups, natural history, the focus remains on specific graded recommendations.

These AGA/AASLD/ACG guidelines do not recommend screening adults due to uncertainties surrounding diagnostic tests and treatment.  This includes high risk populations such as diabetics and bariatric patients.  In addition, unlike recent obesity guidelines from the AAP (Pediatrics 2007; 120: S164-192), these guidelines do not recommend screening children for NAFLD.

Specific management recommendations:

  • Exclude competing etiologies in patients with suspected NAFLD: iron studies, autoantibodies, Wilson’s, viral hepatitis, celiac serology, muscle disease
  • Consider liver biopsy in higher risk patients: metabolic syndrome patients, patients with higher NAFLD Fibrosis score, or before treatment
  • Serum/plasma CK18 is promising biomarker.  Not recommended for routine practice at this time.

Treatment Recommendations:

  • Weight loss (3-5%) helps steatosis and greater losses (up to 10%) may be needed to improve necroinflammation.
  • Metformin –not recommended for liver disease in NASH/NAFLD.
  • Pioglitazone can be used to treat steatohepatitis; however, “long-term safety and efficacy of pioglitazone in patients with NASH is not established.”
  • Vitamin E at 800 units/day improves liver histology in biopsy-proven NASH.  Not recommended without biopsy-confirmed NASH, in diabetic patients, or patients with cirrhosis.  Concern with Vitamin E in adults has been an association with increased all-cause mortality in some studies (but not in others).
  • Avoid alcohol in patients with NAFLD

Website to download PDF version:


Another opinion on which patients to biopsy:


Related posts:

A liver disease tsunami