Stratifying the Risk of Asymptomatic Gallstones

G Morris-Stiff et al. Clin Gastroenterol Hepatol 2023; 21: 319=327. The Natural History of Asymptomatic Gallstones: A Longitudinal Study and Prediction Model

Using a retrospective cohort design with 22,257 patients (51% female) with a mean age of 61 years, Key Findings:

  • There was a 2% per year rate of developing symptomatic gallstones
  • Overall, 14.5% developed symptoms with a median followup of 4.6 years
  • Cumulative incidence of becoming symptomatic: 10.1% at 5 years, 21.5% at 10 years, and 32.6% at 15 years
  • The strongest predictors of developing SGs were female gender (hazard ratio [HR], 1.50), younger age (HR per 5 years, 1.15), multiple stones (HR, 2.42), gallbladder polyps (HR, 2.55), large stones (>9 mm) (HR, 2.03), and chronic hemolytic anemia (HR, 1.90). Elevated BMI was associated with increase risk; for example a BMI >40 had a HR of 1.60.
  • Statin use was associated with a reduced risk of with HR 0.61

My take: This large retrospective study of adults indicates that if given enough time, more than 1/3rd of individuals will develop symptomatic gallstones. Surgical intervention should be considered in those with significant risk factors.

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Which patients with asymptomatic gallstones need a cholecystectomy?

Update: re: Yesterday’s post on tax inversion.  NPR report: Pfizer calls off Allergan Merger due to anti-inversion rules instituted by Treasury Dept


“Generally, the clinical course for the majority of gallstones is asymptomatic…Overall, little knowledge exists about the development into symptomatic disease.”  This introduction from a recent study (DM Shabanzadeh et al. Gastroenterol 2016; 150: 156-67-thanks to Ben Gold for sharing his interest in this study) provides the rationale for their study which analyzed 3 randomly selected groups in Denmark (ages 30-70 years) and followed them for a median of 17.4 years.

Out of an initial 6037 participants, 664 had gallstones at baseline (after excluding 189 who had cholecystectomy and 5180 without gallstones). Only 10% were aware that they had gallstones.

Key findings: 

19.6% developed symptomatic disease (8% complicated, 11.6% uncomplicated)

Risks for symptomatic disease: Female sex, Younger age, Stone size >10 mm, Multiple stones

  • Male with small stone: 2/67 (HR 1.0)
  • Male with multiple stones: 4/97 (HR 1.83)
  • Male with large stone: 2/47 (HR 2.79)
  • Male with multiple and large stones: 3/29 (HR 5.12)
  • Female with small stone: 4/102 (HR 2.16)
  • Female with multiples stones (no large stones) 11/120 (HR 3.96)
  • Female with large stone: 12/67 (HR 6.02)
  • Highest risk: female with multiple stones and with largest stone >10 mm: 10/53(HR 11.05)

Interestingly, the 10% who knew that they had gallstones before randomly being selected  into the study had significantly higher rates of all outcomes, especially uncomplicated events.  “This finding may reflect a protopathic bias.” Patients who were aware were more likely to have suffered bilary colic attacks before study entry and thus had a higher risk of events.

My take: First of all, completion of this study over more than 17 years is an astonishing feat, particularly without informing the participants of their gallstone status.  In patients who are truly asymptomatic, my interpretation would be that only those at substantial risk would benefit from cholecystectomy.  This study does not account for other factors that could favor cholecystectomy (in asymptomatic patients) such as hemolytic diseases (e.g. sickle cell), cystic fibrosis, and other conditions in which symptomatic gallbladder disease is more likely to develop.

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Hunter Museum, Chattanooga

Hunter Museum, Chattanooga

Blood is not enough

…to resolve the problems of sickle cell anemia.  The effects of transfusions for sickle cell patients’ hepatobiliary function are poorly understood.  By lowering the level of hemoglobin S and reducing sickling, can this lead to improvement in organs damaged by sinusoidal congestion and infarction?  Well probably not (J Pediatr 2012; 160: 281-85).

Strokes are known to occur in 5-10% of sickle cell patients by 20 years of age and if untreated, >50% have recurrence.  This has led to transfusion programs.  The ‘Stroke with Transfusions Changing to Hydrdoxyurea’ (SWiTCH) study is a multi-center randomized trial trying to determine how current treatment (transfusions and chelation) compares with hydroxyurea/phlebotomy for preventing stroke and managing iron overload.  As part of this study, a baseline assessment with ultrasound showed widespread problems -despite an average of 7 years of transfusions.  In this cohort of 149 patients, the following findings were identified:

  • Spleen volumes were increased in more than 1/3rd of patients leading to hypersplenism (low platelet counts). 12 subjects had nonvisible spleens due to autoinfarction.
  • Nephromegaly was present.  This finding is known to occur with sickle cell disease and is a marker of glomerular hyperfiltration.
  • Hepatobiliary disease was nearly ubiquitous.  37 of 148 had previous cholecytectomy; of the remaining, 46 of 111 (41%) had gallstones and 14% had gallbladder sludge.  Liver lengths were significantly longer as well.

Conclusions: Transfusion therapy was insufficient to reverse or prevent organ damage in children with sickle cell anemia.  An important limitation– the severity of the underlying prevalence of organ dysfunction prior to initiation of transfusion therapy was not known.

Additional references:

  • -Blood 2011; 117: 772-9.  Silent cerebral infarcts occur despite regular blood transfusions.
  • -Clin Gastro & Hep 2007; 5: 1469.  Reviews types of sickle cell associated liver disease.
  • -Pediatric Hematology and Oncology.  2006 Mar;23(2): 95-102(8).  Sickle cell intrahepatic cholestasis (SCIC), which is related to intrahepatic sinusoidal RBC sickling (due to relative hypoxia) and can be associated with progressive hepatomegaly, mild transaminitis, extreme hyperbilirubinemia
  • -JPGN 2004; 39: 200.  Review of sickle cell hepatic crisis.  Cholestasis resolves over 3 months.  Acute crisis treated with hyperhydration & transfusion. Cohort of 350; 6 developed hepatic crisis.
  • -J Pediatr 2001; 139: 785-789 & 790-796.  Transfusions and hydroxyurea for SS dz.