Pathophysiology of Lactose Intolerance and Metabolic Alterations
There are five causes of hypolactasia: (1) congenital loss (very rare); (2) inherited loss on weaning, very common; (3) gut infections, such as rotavirus and Giardia (a monocellular parasite; see chapter “Gastroenteritis”); (4) damage to the villi in the small intestine caused by radiotherapy or bacterial overgrowth; and (5) hormonal disturbance (e.g., thyroid), menopause, and aging.
The first two of these are irreversible. In contrast, the last three potentially are reversible , after recovery from the gut infection, repair of damage to the villi, or treatment of the hormonal disturbance. Almost all mammals lose lactase after weaning . Thus, inherited hypolactasia is very common, being as high as 90 % in Chinese and >80 % in Asians . In evolution, apes would never see milk after coming off the mother's breast. Lactase persistency in adult humans is only present in some ethnic groups, such as Bedouins and Northern Europeans (in which it reaches 90 %). Sensitivity to lactose generally increases with southern origins.
The loss after weaning correlates with two polymorphisms – C/T13910 and G/A22018 – occurring within introns of a helicase, upstream from the lactase gene on the long arm of chromosome
2 . There is close correlation between the level of lactase and the C and G genotypes, those with CC and GG having the lowest levels. The molecular basis of this correlation is unknown. But, the key is the number of cells expressing lactase rather than the level of lactase in each cell . In Chinese, the loss of lactase can be
>90 % by the age of 5 years, but in other races it may take until teenage before the nadir of lactase is reached .
Hypolactasia causes a maldigestion of lactose in the small intestine. Lack of lactose uptake does not cause severe symptoms as the human body does not require lactose as such and can synthesize galactose in some non-mammary cells if required. However, undigested lactose is transported to the colon where it is subject to degradation by bacteria or archaeans forming gases such as hydrogen or methane and metabolic toxins such as methylglyoxal and other alcohols, diols, aldehydes, ketones, and acids . Due to the variable tolerance of lactose between individuals  and the different degradation products, the resulting symptoms vary in type and severity (Fig. 1) .
Gas in the large intestine causes gut symptoms, like distension, borborygmi, and flatulence. Moreover, the metabolic toxins affect the balance of microflora in the gut and cause diarrhea or constipation. This surprising difference between diarrhea or constipation in particular patients reflects whether the bacterial metabolic toxins act to block smooth muscle contraction, and thus cause constipation, or act in an analogous way to cholera or enterotoxin to signal fluid secretion into the large intestine. After absorption into the blood, the bacterial metabolic toxins result in a multitude of systemic symptoms in peripheral tissues, ranging from fatigue, headache, cognitive dysfunction, muscle and joint pain to heart palpitations, exacerbation of allergies  (see chapter “Allergies”), and liver and kidney problems (see chapters “Overview” under the part . Most prominently, methylglyoxal reacts with hormones (e.g., insulin) and neurotransmitters (e.g., serotonin and dopamine), inactivating them , a biochemical process called Pictet-Spengler reaction. Methylglyoxal also acts on neurons directly, causing pain.
Lactose intolerance is associated with IBS  and IBD . The symptoms in IBS are a result of poor lactose digestion and sugar absorption in the small intestine. In IBD, it is not clear whether lactose intolerance is a cause or consequence of the intestinal inflammation. Although there are endogenous mechanisms capable of inactivating bacterial toxins, their role in lactose intolerance, IBS, and IBD is as yet unknown.